Membranes And Receptors Flashcards

Question 1

Q

What is the composition of biological membranes?

Answer

A

40% lipid
60% protein
1-10% carbohydrates

Hydrated structure- 20% of total weight is due to WATER

Question 2

Q

What are the 5 main functions of biological membranes?

Answer

A

Permeability barrier -highly selective and continuous
Control of enclosed chemical environment
Communication
Recognition- signalling molecules, adhesion proteins and immune surveillance
Signal generation in response to stimuli (electrical and chemical)

Question 3

Q

Why do biological membranes vary in structure and composition?

Answer

A

Different regions of plasma membrane may have different functions (e.g transport, secretion, synapses, absorption of body fluids, electrical signal conduction…)

Question 4

Q

What are the main membrane lipids?

Answer

A

Phospholipids- phosphatidylcholine

Plasmalogens- sphingomyelin, glycolipids, cholesterol

Question 5

Q

What are the two basic structures of membrane lipids?

Answer

A

Micelles

Bilayer

Question 6

Q

In a membrane bilayer, what forces are present?

Answer

A

Hydrophilic regions- electrostatic and H bonding

Hydrophobic regions- vdW forces

Question 7

Q

What does it mean, that membrane lipids are AMPHIPATHIC?

Answer

A

Membrane lipids have hydrophobic and hydrophilic regions

Question 8

Q

Which membrane lipid is the most common?

Answer

A

Phospholipids

Question 9

Q

What is the arrangement of phospholipids?

Answer

A

Head group
Phosphate group (C3 of glycerol)
Glycerol
2 Fatty acid chains (C1 and 2 of glycerol)

Question 10

Q

What head groups are common in phospholipids?

Answer

A

Choline, sugars, amino acids, amines
Choline
Serine
Ethanol amine
Inositol

Question 11

Q

How many carbons are there in a fatty acid chain in a phospholipid?

Answer

A

C14 - C24

Most common - C16 & C18

Mosty both will be of similar lengths to maintain membrane thickness

Question 12

Q

What is a property of the fatty acid chains in phospholipids?

Answer

A

They can be unsaturated- so have a KINK due to the cis double bond

Question 13

Q

What is the head group in phosphatidylcholine?

Question 14

Q

How do you name phospholipids?

Answer

A

Phosphatidyl + name of head group

Question 15

Q

What is the structure of sphingomyelin?

Answer

A

Resembles phospholipids but NOT based on glycerol

Can interact with phospholipids

Question 16

Q

What is the structure of glycolipids?

Answer

A

Same structure of sphingomyelin (no glycerol) but phosphate and head group are replaced with a monomer of sugar (CEREBROSIDE) or an oligosaccharide (GANGLIOSIDE)

Question 17

Q

What is the structure of cholesterol?

Answer

A

Polar head group (OH)
4 ring rigid planar steroid structure
Non polar hydrocarbon tail
Makes up to 45% of total membrane lipid

Question 18

Q

What bonds does cholesterol form with adjacent phospholipids in a membrane?

Answer

A

Forms H bonds between the OH of cholesterol and fatty acid chains (ester bonds) of phospholipids

Question 19

Q

How does cholesterol increase fluidity and at what temperature?

Answer

A

At low temperatures
More cholesterol means that less energy is required to maintain the membrane fluidity as cholesterol prevents the formation of crystalline structures of lipids in the bilayer

Question 20

Q

How does cholesterol decrease membrane fluidity and at what temperature?

Answer

A

At high temperature
Rigid cholesterol structure is held close to fatty acyl chains
- reduces intrachain vibrational movements

Question 21

Q

What are the main movements of membrane lipids?

Answer

A

Flexion (vibration)
Rotation
Lateral diffusion
Flip flop (rare)

Question 22

Q

Why is flip flop of membrane lipids rare?

Answer

A

Takes hydrophilic group into a hydrophobic domain

Question 23

Q

What is the functional evidence for membrane proteins?

Answer

A

Facilitated diffusion
Ion gradients
Specificity of cell responses

Question 24

Q

What is the biochemical evidence for membrane proteins?

Answer

A

Membrane fractionation and gel electrophoresis

Freeze fracture

Question 25

Q

What are the main movements of membrane proteins?

Answer

A

Conformational change- vibration
Rotational
Lateral
NO FLIP FLOP

Question 26

Q

What is the evidence for lateral movement of membrane proteins?

Answer

A

Mouse and human hybrid cells

Question 27

Q

Why can’t membrane proteins move by flip flop?

Answer

A

Due to the thermodynamic constraints of moving large hydrophilic groups through the hydrophobic core

Question 28

Q

What are some restrictions of protein mobility in membranes?

Answer

A

Proteins tend to separate into cholesterol rich fluid phases and cholesterol poor crystalline structure phases - LIPID MEDIATED EFFECTS - AGGREGATES
Associations with membrane proteins on other cells- CLUMPING
Associations with extra membranous proteins - TETHERING - fixes proteins in fixed positions to basement membrane, peripheral proteins or cytoskeleton

Question 29

Q

Membrane proteins cane be…?

Answer

A

Peripheral

Integral - intrinsic (completely span the membrane) and extrinsic (don’t completely span the membrane)

Question 30

Q

Describe peripheral proteins

Answer

A

Bounds the surface of membranes
Bonds- electrostatic and H bonding interactions
Removed by changes in pH or in ionic strength

Question 31

Q

Describe integral proteins

Answer

A

Interact extensively with hydrophobic domains of lipid bilayer (intrinsic and extrinsic)
Cannot be removed by manipulation of pH and ionic strength
Removed by agents that compete for non polar interactions - detergents and organic solvents
Alpha helical arrangement across hydrophobic region of membrane
R groups in hydrophobic region are largely hydrophobic (on outside of helix)

Question 32

Q

Why is it important that membrane proteins can be asymmetric?

Answer

A

For function- receptors

E.g. Insulin receptor must have recognition site directed to extracellular space

Question 33

Q

Describe the arrangement of the cytoskeleton of an erythrocyte

Answer

A

Peripheral proteins in cytoplasmic surface-
Spectrin
Cross linked spectrin rods- actin, band 4.1 and adducin
Adapter proteins- ankyrin and band 4.1

Integral proteins- 
Band 3 (Anion exchanger) and band 7 (glycoporphorin A)

Example of tethering

Question 34

Q

Why must peripheral proteins be located on the cytoplasmic side in the cytoskeleton of erythrocytes?

Answer

A

They are susceptible to proteolysis only when the cytoplasmic face of the membrane is accessible

Question 35

Q

How do integral proteins affect cytoskeleton of erythrocyte membrane mobility?

Answer

A

Attachment of integral membrane proteins to the cytoskeleton restricts the LATERAL mobility of the membrane protein

Question 36

Q

What is haemolytic spherocytosis?

Answer

A

When spectrin is depleted by 40-50%
Erythrocytes round up and become less resistant to lysis
Erythrocytes are cleared by the spleen
SPHERICAL RBCs
=tiredness, low O2 delivery, treated with transfusion in crisis

Question 37

Q

What is hereditary elliptocytosis?

Answer

A

Defect in spectrin molecule
Unable to form heterotetramers
Fragile elliptoid cells
ELLIPTICAL RBCs

Question 38

Q

Describe the synthesis of membrane proteins

Question 39

Q

What is a multiple trans membrane domains?

Answer

A

Where a protein has multiple trans membrane domains (e.g G coupled protein receptors- 7)
It is likely that the folding of the nascent protein against the constraint of the first trans membrane segment is the driving force for the insertion of the other domains

Question 40

Q

What graph can be used to show the structure of transmembrane proteins?

Answer

A

Hydropathy graph / plot

Question 41

Q

What molecules can pass through membranes freely?

Answer

A

Hydrophobic molecules (oxygen, Carbon dioxide, nitrogen, benzene)
Small uncharged polar molecules (water, urea, glycerol)

Question 42

Q

What molecules cannot pass through membranes freely?

Answer

A

Large uncharged polar molecules (glucose and sucrose)

Ions (H+, Na+, K+, Ca2+, Mg2+, Cl-, HCO3-)

Question 43

Q

What are some important roles of transport process?

Answer

A

Maintenance of ionic composition
Maintenance of IC pH
Regulation of cell volume
Concentration of metabolic fuels and building blocks
Extrusion of waste products of metabolism and toxic substances
Generation of ion gradients necessary for the electrical excitability of nerve and muscle

Question 44

Q

What is passive diffusion?

Answer

A

Dependent on permeability and concentration gradient
Rate of passive transport increases linearly with increasing conc gradient
PASSIVE (does not require energy), uses CHANNELS

Question 45

Q

What is facilitated diffusion?

Answer

A

Permeability of the membrane for a substance is increased by the incorporation of a specific protein in the bilayer:
Carriers molecules (ping pong proteins) 
Ion protein channels (ligand gated or voltage gated)

Saturable process - each carrier can interact with a few ions or molecules at any given moment

CARRIERS AND CHANNELS, PASSIVE (no energy)

Question 46

Q

What is active transport?

Answer

A

Allows the transport of ions or molecules against an unfavourable concentration and or electrical gradient requiring energy (directly or indirectly) the hydrolysis of ATP (30-50% cells ATP used on at)
Whether or not energy is required depends on the free energy change of the transported species and by the electrical potential across the membrane bilayer when the transported species is charged

Question 47

Q

What are the main channels and what processes are they used in?

Answer

A

Uni port channel
Gated ion channel
Ligand gated ion channel (nicotinic acetlycholine receptor, ATP sensitive K+ channel)
Voltage gated ion channel (Na+ channel)

Passive diffusion and facilitated diffusion

Question 48

Q

What are the main carriers and what processes are they used in?

Answer

A

Ping pong transporters
Co transporters ( more than one type of ion or molecule may be transported on a membrane transporter per cycle)
= symport (two molecules, same direction) (Na+ glucose)
= anti port (two molecules, different direction) (Na+ Ca2+ exchange OR Na+ H+ exchange)

Question 49

Q

Describe the sodium potassium pump

Answer

A

A plasma membrane associated pump
Uses ATP to pump ions (active transport)
25% of BMR is used for pump
Called a P-type ATPase
(ATP phosphorylates Aspartate, producing phosphoenzyme intermediate)
a-Subunit – Binding sites for K+, Na+, ATP, ouabain
b-Subunit – Glycoprotein directs pump to the surface
The binding of ouabain to the a-Subunit inhibits Na+/K+-ATPase
Uses energy from ATP hydrolysis to move 2K+ into the cell and 3Na+ out of the cell. (Antiport)
Forms Na+ and K+ gradients
Necessary for electrical excitability
Drives Secondary Active Transport
Control of pH
Regulation of cell volume
Regulation of Ca2+ concentration
Absorption of Na+ in epithelia
Nutrient uptake, e.g. glucose from the small intestine

Question 50

Q

Describe the PMCA

Answer

A

Plasma Membrane Ca2+-ATPase (PMCA)

Expels Ca2+ bound to calmodulin from the cell in exchange for H+
Uses ATP
Antiport
High affinity, low capacity
Removes residual Ca2+

Question 51

Q

Describe the SERCA

Answer

A

Accumulates Ca2+ bound to calmodulin into the SR/ER in exchange for H+

Uses ATP
Antiport
High affinity, low capacity
Removes residual Ca2+

Question 52

Q

Describe the NCX

Answer

A

Na+/Ca+-exchanger (NCX)

Secondary Active Transport
Expels 1xCa2+ from the cell in exchange for 3xNa+
Uses the Na+ concentration gradient set up by Na+/K+-ATPase
Antiport
Low affinity, high capacity
Removes most Ca2+
Electrogenic – Current flows in the direction of the Na+ gradient
Expels intracellular Ca2+ during cell recovery
Activity is membrane potential dependent

Question 53

Q

Describe the NHE

Answer

A

Na+/H+ Exchanger (NHE)

Exchanges extracellular Na+ for intracellular H+
Electroneutral 1:1 exchange
Uses the Na+ concentration gradient set up by Na+/K+-ATPase
Raises intracellular pH
Regulates cell volume
Activated by growth factors
Inhibited by amiloride

Question 54

Q

Describe the bicarbonate transporters: NBC and AE

Answer

A

Sodium Bicarbonate Co-Transporter (NBC)
Na+ Dependent Cl-/HC03- Exchanger
- Acid out
- Base in
- Uses the Na+ concentration gradient set up by Na+/K+-ATPase
- Raises intracellular pH
- Both involved in regulating cell volume
- acid extruder
- Na+ and HCO3- in and H+ and Cl- out

Anion Exchanger (AE)
Cl-/HCO3- exchanger
- Removes base from cell
- Acidifies cell
- Involved in cell volume regulation
- Base extruder

Question 55

Q

What inhibits the sodium potassium pump?

Question 56

Q

What inhibits the NHE?

Answer

A

Amiloride

Question 57

Q

What two transporters are acid extruders?

Question 58

Q

What transporter is a base extruder?

Question 59

Q

What transporters are involved in the control of resting [Ca2+]?

Answer

A

Sodium potassium pump (sets up the gradient for NCX)
PMCA
SERCA
NCX
Ca2+ uni porters into mitochondria

Question 60

Q

What transporters are involved in regulation of cellular pH?

Answer

A

Sodium potassium pump (all cells)
NHE (most cells) - acidic extrusion
NBC (some cells) - acid extrusion and alkali influx
Na+-3HCO3- co transport (some cells) - alkali influx
AE (most cells) - alkali extrusion

Question 61

Q

What mechanisms are involved in regulation of cell volume?

Answer

A

Mechanisms to resist cell swelling-
Efflux of osmotically active ions ( sodium, potassium, chloride) or solute molecules
Water follows

Mechanisms to resist cell shrinking-
Influx of osmotically active ions (sodium, potassium, chloride)
Water follows

Question 62

Q

Describe bicarbonate resorption by the proximal tubule

Answer

A

Na/K pump again drives other channels, by keeping intracellular Na+ concentration low, so NHE can pump H+ ions into the proximal tubule lumen.

H+ goes into the lumen to “pick up” bicarbonate and bring it back into the cell.

Under normal corcumstances the kidney reabsorbs all the bicarbonate filtered into the proximal tubule
The main reason is to retain base for the pH buffer
E.g. Renal control of circulating sodium conc is often a first line treatment for mild hypertension
Water tablet- diuretic

Question 63

Q

Outline renal Na+ handling, diuretics and Anti-Diuretics

Answer

A

The goal of Renal anti-hypertensive therapy is to reduce the reuptake of Na+ and other molecules, so less water is reabsorbed via osmosis.

With less water being reabsorbed, blood volume and therefore blood pressure falls

Aquaporin allows water to more readily cross the membrane. Its inclusion in the mmebrane is stimulated by anti-diuretic hormone (ADH)

Loop diuretics block Na+ reuptake in the thick ascending limb

Amiloride acts both in the Distal convoluted tubule (ENaC) and the proximal tubule (Na/H) to prevent Na+ reuptake

Aldosterone up-regulates these transporters.
Spironolactone (Glucocorticoid receptor antagonist) is used to treat (if Aldosterone is high)

Question 64

Q

Describe transporters in cystic fibrosis

Answer

A

Transport of Na+ out of cell by Na/K pump allows for the symport of 2Cl- out of the cell with Na+ and K+.

Faulty CFTR protein leads to accumulation of Cl- in the cell.
Water moves into the cell via osmosis, giving thick, viscous mucous in the lumen.

Answer 60

A

CFTR is overly active once phosphorylated by Protein Kinase A.

Cl- is excessively transported into the lumen.

Water follows, giving the symptoms of Diarrhoea.

Answer 61

A

Electrical potential (voltage) difference across the plasma membrane of a cell

Answer 62

A

Provides the basis of signalling in the nervous system, heart and other tissues

Answer 63

A

Always expressed as the potential inside the cell relative to the extracellular solution

Answer 64

A

Millivolts

Answer 65

A

Using a very fine micropippette- microelectrode that will penetrate the cell membrane
Tip diameter < 1 micrometer
Microelectrode is filled with a conducting solution (KCl)

Answer 66

A

Membranes have different selective permeabilities for different ions due to the presence of channel proteins (which are selective for specific ions)

Answer 67

A

Selectivity- the channel lets through only one (or a few) ion species (e.g. Specific to Na+ Ca2+ K+ Cl- and with non selective cation permeability)
Gating- channel can be open or closed by a conformational change in the protein molecule
A high rate of ion flow- always down the concentration gradient (passive)

Answer 68

A

Ligand gated
Voltage gated
Mechanical gated

Answer 69

A

Chemical ligands bind causing a conformational change and causing the gates to open or close

E.g. Channels at synapses that respond to EC transmitters
Channels that respond to IC messengers

Answer 70

A

Change in membrane potential causing the channel to open or close

E.g. channels involved in action potentials

Answer 71

A

Membrane deformation causing the channels to open or close

E.g. Channels in mechanoreceptors carotid sinus stretch receptors: hair cells

Answer 72

A

Provides the outward ionic gradient for K+ necessary for maintenance of the membrane potential
Although electrogenic, (3Na+ out 2K+ in) the enzyme contributes little to the membrane potential (-5mV)
So indirectly Na+ K+ ATPase pump (active transport) is responsible for entire membrane potential because it sets up and maintains ionic gradients K+

Answer 73

A

Voltage insensitive K+ channels (facilitated diffusion), which remain open despite the changes in potential across the membrane, are responsible for K+ movement that establishes the resting membrane potential
ICK+ 160mmol/l
ECK+ 4.5mmol/l
K+ moves outwards down the concentration gradient
Since large anions can’t follow as they can’t penetrate the membrane, a negative potential develops on the intracellular face of the plasma membrane
Growing potential difference across the membrane then opposes the further efflux of K+
An equilibrium is reached when the chemical and electrical forces are balanced and there is no net movement of K+

Answer 74

A

At equilibrium, the electrical and chemical gradients for K+ balance so that there is no net driving force on K+ across the membrane
Nernst equation allows us to calculate the membrane potential. At which K+ will be in equilibrium given the extracellular and intracellular K+ concentrations
Looks at K+ alone
~-95mV

Answer 75

A

Ek= 61/z log(10) [K+]o/[K+]i 
Z= valency

Answer 76

A

Corresponds to an estimate of the resting membrane potential (assuming there are no other channels in the membrane- obviously not true and so actual resting membrane potential is always slightly different)

Answer 77

A

Plasma membrane is not totally impermeable to other ions and the passage of these ions through selective ion channels contributes to overall membrane potential
Depends on number of ions, concentration of ions, type of ion, selectivity of channels etc.

Answer 78

A

A decrease in the size of the membrane potential from its normal value
Cell interior becomes less negative
Opening Na+ and Ca2+ channels (influx of Na+ and Ca2+)

Answer 79

A

An increase in the size of the membrane potential from its normal value
Cell interior becomes more negative
Opening K+ or Cl- channels (out flux of K+ and influx of Cl-)

Answer 80

A

Signalling
Action potentials in nerve and muscle cells
Triggering and control of muscle contraction
Control of secretion of hormones and neurotransmitters
Transduction of sensory info into electrical activity by receptors
Post synaptic actions of fast synaptic transmitters

Answer 81

A

Have an intrinsic ion channel
Opened by binding of ACh
Channels let Na+ K+ through, but not anions
Moves membrane potential towards 0mV = intermediate between ENa+ and EK+
Sodium predominates movement across membrane

Answer 82

A

At the synapse a chemical transmitter is released from the presynaptic cell and binds to receptors on the post synaptic membrane
Fast synaptic transmission
Slow synaptic transmission

Answer 83

A

Receptor protein is also an ion channel
Transmitter binding causes channel to open

Excitatory synapse- open ligand gated channels, depolarisation, Ca2+ and Na+, change in membrane potential = excitatory post synaptic potential (EPSP)
(Longer than ap, graded with amount of transmitter, ACh, Glutamate (transmitters))

Inhibitory synapse- open ligand gated channels, hyper polarisation, K+, Cl-, change in membrane potential = inhibitory post synaptic potential (IPSP)
(Glycine, gamma amino butyric acid GABA)

Answer 84

A

Receptor protein and channel protein are separate
Direct G protein gating- localised and quite rapid (1 signal = 1 event)
Gating via an intracellular messenger- throughout cell, amplification (1 signal= many events)

Answer 85

A

High concentration of potassium in the blood
Less negative EK resting membrane potential
So lesser change in ion conductance is required to depolarise the heart and so excite cardiac membranes - ventricular arrhythmia (life threatening)
Na+ channels become inactivated more rapidly
Less negative membrane potential also prevents the repriming of inactivated Na+ channels resulting in an electrically silent membrane - also contributes to arrhythmia

Answer 86

A

Change in voltage across the membrane

Answer 87

A

Ionic gradients

Relative permeability of the membrane

Answer 88

A

Voltage sensitive sodium channels

Answer 89

A

The membrane potential will move closer to the equilibrium potential for that ion

Answer 90

A

It is dependent on the number of channels for that ion that are open

Answer 91

A

Enables the membrane current to be measured at a set membrane potential
By voltage clamping which controls the membrane potential so that the ionic currents can be measured
Using different ionic concentrations the contribution of various ions can be assessed
Patch clamping enables current flowing through individual ion channels to be measured

Answer 92

A

In an unclamped cell membrane potential can change freely

Voltage clamp prevents change in membrane voltage in response to membrane current

Answer 93

A

The initiation of an action potential depends on the membrane potential rising above a threshold value

Answer 94

A

An increased open probability for Voltage gated sodium and calcium channels which lead to membrane depolarisation to exceed the hyperpolarising effects of the resting potassium efflux

The closure of potassium channels which reduces the hyperpolarising effect on membrane allowing the membrane potential to rise in the leak of sodium and calcium

Answer 95

A

Depolarisation to threshold 
Sodium channels open
Sodium enters the cell
Membrane depolarises
Causes more sodium channels to open 
Positives feedback is the basis of all or nothing characteristic of the action potential

Answer 96

A

Depolarisation causes Potassium channels to open causing a potassium efflux and repolarisation
Depolarisation inactivates sodium channels causing the influx of sodium to be stopped and thus repolarisation

Answer 97

A

Absolute refractory period

Relative refractory period

Answer 98

A

During the peak
When excitability is Zero
When nearly all the sodium channels are in the inactivated state
Another AP cannot be generated here

Answer 99

A

After the Peak
When excitability is increasing
When sodium channels are recovering from inactivation (ie. returning to closed state so that they are available for another) excitability returns towards normal as the number of channels in the inactivated state decreases
Another AP can be generated here

Answer 100

A

Yes however it is more difficult to reach the threshold

Answer 101

A

The longer the stimulus is, the larger the depolarisation necessary to initiate an action potential
With a persistent stimulus, sodium channels become inactivated and the threshold becomes more positive (as less sodium channels are available to be opened)
(If a stimulus lasts a long time the body becomes used to it and so a greater depolarisation is needed to isolate an action potential)

Answer 102

A

One peptide
4 homologous repeats
Six transmembrane domains
One domain is voltage sensitive S4
Function requires one subunit

Answer 103

A

Are similar in structure but each repeat is in fact a separate sub unit
4 peptides
Six transmembrane domains
One domain is voltage sensitive S4
Function requires 4 subunit

Answer 104

A

Procaine

It stops action potential generation

Answer 105

A

Small myelinated axons (sensory)
Non myelinated axons
Large myelinated axons (motor)

Answer 106

A

Local anaesthetics are weak bases and cross the membrane in their unionised form- they block sodium channels when the channel is open and also have a higher affinity to the inactivated state of the sodium channel
Stop action potential generation
Via hydrophobic or hydrophilic pathway

Answer 107

A

Occurs under a cathode (negative)
Excitability will be reduced under an anode (positive)
Electrodes can be used to raise the membrane potential to threshold to generate an action potential
By recording changes in potential between the STIMULATING (cathode -ve) and RECORDING (anode +ve) electrodes along an axon, conduction velocity can be calculated
Extracellular recording of action potentials can give info about the conduction velocities under various conditions

Answer 108

A

Conduction velocity= distance/ time

Measuring the distance between the stimulating electrode and the recording electrode and the time gap between the stimulus and action potential being registered by the recording potential

Answer 109

A

The depolarisation of a small region of membrane produces transmembrane currents in neighbouring regions
As sodium channels are voltage gated this opens more channels causing the propagation of an action potential
The further the local current spreads the faster the conduction velocity of the axon

Answer 110

A

A high membrane resistance
A low membrane capacitance
A large axon diameter

Answer 111

A

Membrane resistance depends on the number of ion channels open
So the higher the membrane resistance, the more sodium channels open, the easier to reach threshold

Answer 112

A

Capacitance is the ability to store charge
So membrane with low capacitance will take less time to charge as its ability to store charge will be less, increasing conduction velocity

Answer 113

A

Results in a low cytoplasmic resistance
Current is thus larger
Action potential will travel further
Increased conduction velocity

Answer 114

A

Ability to store charge

Answer 115

A

Myelinated axon- cv dp to diameter
Unmyelinated axon - cv dp to square root (diameter)
Diameter is limiting for the myelinated axon when small

Answer 116

A

Oligodendrocytes

Answer 117

A

Schwann cells

Answer 118

A

Conduction velocity is increased considerably by myelination of axons

Answer 119

A

It reduces membrane capacitance

Increasing conduction velocity

Answer 120

A

It increases the membrane resistance

Increasing conduction velocity

Answer 121

A

In myelinated axons

Where action potential jumps between nodes of Ranvier

Answer 122

A

Myelin acts as a good insulator, causing local circuit currents to depolarise the next node above threshold and generate an action potential

Answer 123

A

Nodes are a high density of sodium voltage gated channels

Evenly distributed in unmyelinated neurones

Answer 124

A

Demyelination
Autoimmune disease where myelin is destroyed in certain areas of the CNS
decreased conduction velocity

Answer 125

A

Na+ K+ ATPase pump

Answer 126

A

Na+ Ca2+ exchange NCX

Answer 127

A

NKCC2 furosemide

Answer 128

A

NCC on distal convoluted tubule

Hydrochlorothiazide

Answer 129

A

Na+ K+ Ca2+

Answer 130

A

Action potential arrives at nerve terminal
Depolarisation causes the opening of voltage gated calcium channels
Influx of calcium
Rise in intracellular concentration of calcium causes release of neurotransmitter

Answer 131

A

Calcium binds to synaptotagmin
Vesicle is brought close to the membrane and binds to the snare complex
Snare complex makes a fusion pore with the membrane
Transmitter (acetyl choline) is released through this pore

Answer 132

A

1 x 10 ^-7 M

Answer 133

A

1 x 10 ^-3 M

Answer 134

A

Exocytosis

Answer 135

A

Very similar structurally to sodium vg channels
BUT calcium has some structural diversity in that a blocker that blocks one calcium channel will not necessarily block another
Different calcium channels have different primary locations so selectively blocking one type of channel can have a localised effect

Answer 136

A

DHP Dihydropyridine (e.g. nifedipine)

Answer 137

A

All muscles, neurones, lungs

Answer 138

A

w-CTx-GVIA

Answer 139

A

R- neurones/heart?

T- neurones/ heart (SAN)

Answer 140

A

Nicotinic ACh receptor

Answer 141

A

Ligand gated ion channels

Answer 142

A

End plate potential

Answer 143

A

This depolarisation will raise the muscle above threshold so that an action potential is produced as it activates adjacent sodium channels and potassium channels due to the local spread of charge

Answer 144

A

ACh esterase

Answer 145

A

Fast synaptic transmission

Answer 146

A

Competitive blockers bind to the molecular recognition site for ACh
Tubocurarine

Answer 147

A

Depolarising blockers cause a maintained depolarisation at the post junctional membrane. Adjacent sodium channels will not be activated due to accommodation
Succinylcholine (used in operations to induce paralysis)

Answer 148

A

Autoimmune disease causing the destruction of nicotinic ACh receptors
Caused by antibodies directed against nAChRs on the post synaptic membrane of skeletal muscle
End plate potentials are reduced in amplitude, leading to muscle weakness and fatigue

Answer 149

A

Drooping eyelids
Profound weakness, which increases with exercise
Fatigue

Answer 150

A

Using AChesterase inhibitors, increasing the amount of time ACh remains in the synaptic cleft and hence increasing the likelihood of ACh binding to any remaining available receptors

Answer 151

A

Slow synaptic transmission

mACh receptors are coupled to G proteins which trigger a cascade of events in the cell

Answer 152

A

Many cellular processes are calcium sensitive, for example fertilisation, secretion, neurotransmission, metabolism, contraction, learning and memory, apoptosis and necrosis. As Ca2+ cannot be metabolised, the cell has to regulate intracellular Ca2+ concentration based largely on moving Ca2+ into and out of the cytoplasm.

Answer 153

A

Changes in intracellular [Ca2+] occur rapidly with little movement

Answer 154

A

Ca2+ overload leads to loss of regulation and cell death

Answer 155

A

The relative impermeability of the plasma membrane
The ability to expel Ca2+ across the plasma membrane using:
- Ca2+ ATPase
- Na+-Ca2+ Exchanger
Ca2+ Buffers
Intracellular Ca2+ Stores:
- Rapidly releasable
- Non-Rapidly releasable

Answer 156

A

The permeability of the membrane is regulated by the open/closed state of ion channels.

Answer 157

A

Ca2+ ATPase PMCA & SERCA
Considered to be high affinity, low capacity.
- Intracellular [Ca2+] Increases
- Ca2+ binds to calmodulin – a binding trigger protein
- Calmodulin-Ca2+ binds to Ca2+ ATPase
- Ca2+ is removed from cell

Na+/Ca2+ Exchanger
Considered to be low affinity, high capacity
- Na+ Gradient used as driving force (Na+/K+-ATPase) (M&R LO 2.3)
- Transports 3Na+ into the cell per 1Ca2+ out
- Antiporter is electrogenic
- Works best at resting membrane potential

Answer 158

A

Ca2+ buffers limit diffusion, through ATP and Ca2+ binding proteins such as parvalbumin, calreticulin, calbindin and calsequestin.
Diffusion depends on the concentration of binding molecules and their level of saturation.
Many other proteins also bind Ca2+, altering their function, e.g. calmodulin.

Answer 159

A

LARGE INWARD GRADIENT

Answer 160

A

Stores are either rapidly releasable or non rapidly releasable
An alternative way of raising cellular calcium concentration

Answer 161

A

Ca2+ influx across the plasma membrane (Altered permeability)
- Voltage Operated/Gated Ca2+ channels (VOCC/VGCC)
- Receptor operated ion channels (Ionotropic receptors)
Ca2+ release from ‘rapidly-releasable’ stores
- G-protein coupled receptors (GPCRs)
- Ca2+ induced Ca2+ release (CICR)
Ca2+ release from ‘non-rapidly releasable’ stores

Answer 162

A

Voltage-Gated Calcium Channels (VGCC)
Channels that open to allow the influx of calcium down its concentration gradient, triggered by membrane depolarisation.

Receptor Operated Ca2+ Channels
A ligand/agonist binds to the channel, opening it and allowing Ca2+ to enter down its concentration gradient.

Answer 163

A

Stores of Ca2+ are set up inside the Sarco/Endoplasmic Reticulum by the SERCA protein (Sarco/Endoplasmic Reticulum Ca2+ ATPase). Ca2+ is moved in using the energy from ATP hydrolysis and binds to proteins such as calsequestrin.

G-Protein Coupled Receptors (GPCRs)
A ligand binds to the GPCR on the cell membrane, activating its Gaq subunit. This subunit then binds to the membrane phospholipid PIP2, releasing IP3, which in turn binds to its receptor on the sarcoendoplasmic reticulum, triggering the release of calcium down its concentration gradient into the cell.

Ca2+ induced Ca2+ release (CICR)
Ca2+ binds to the Ryanodine receptor on the side of the Sarco/endoplasmic reticulum, triggering the release of calcium down its concentration gradient into the cell.

Answer 164

A

G-Protein Coupled Receptors (GPCRs)
A ligand binds to the GPCR on the cell membrane, activating its Gaq subunit. This subunit then binds to the membrane phospholipid PIP2, releasing IP3, which in turn binds to its receptor on the sarcoendoplasmic reticulum, triggering the release of calcium down its concentration gradient into the cell.

Answer 165

A

Ca2+ induced Ca2+ release (CICR)
Ca2+ binds to the Ryanodine receptor on the side of the Sarco/endoplasmic reticulum, triggering the release of calcium down its concentration gradient into the cell

Answer 166

A

An example of an important physiological role for CICR is in the cardiac myocyte. Here, Ca2+ entry through VOCCs following depolarisation of the membrane binds to the ryanodine receptors, causing an explosive release of large amounts of Ca2+ from intracellular stores.

Answer 167

A

Ca2+ entry through VOCCs following depolarisation of the membrane binds to the ryanodine receptors, causing an explosive release of large amounts of Ca2+ from intracellular stores (CICR)
During the very early part of the action potential (at the height of depolarisation) conditions will favour the reversal of the sodium calcium exchanger (NCX) which will result in a small amount of Ca2+ entry
As the intracellular concentration of calcium increases and membrane repolarisation starts, the sodium calcium exchanger (NCX) will revert to Ca2+ extrusion to lower the intracellular concentration of calcium
Calcium will also be pumped back into the SR are by SERCA in preparation for another release event

Answer 168

A

Ca2+ is taken up into mitochondria when [Ca2+]I is high as a protective mechanism, but mitochondria also participate in normal Ca2+ signalling due to microdomains (areas of cytoplasm with a higher concentration of Ca2+ due to their proximity to a channel).

Mitochondria take up Ca2+ to aid in buffering, regulating signalling, and stimulation of ATP production. They do this via a Ca2+ uniporter that is driven using respiration.

Answer 169

A

Repetitive signalling requires a return to the basal state. Further to this, too much Ca2+ for too long is toxic to cells.

A return to basal levels requires:

Termination of signal
Ca2+ Removal- Ca2+ ATPase and NCX
Ca2+ store refilling- Ca2+ stores are refilled both by the recycling of cytosolic Ca2+ (SERCA) (e.g. cardiac myocyte) and by using Calcium stored in mitochondria. Mitochondrial Ca2+ is used to replenish SR stores via the store-operated Ca2+ channel (SOC).

Answer 170

A

PMCA
SERCA
NCX
Mitochondrial calcium uptake
Calcium binding protein

Answer 171

A

Inositol 1,4,5 triphosphate receptors (IP3) (GPCR)
Ryanide receptors (CICR) 
Voltage sensitive calcium channels (VOCC/VGCC)
Sodium calcium exchanger (NCX) 
Ligand gated calcium channels

Answer 172

A

Voltage sensitive calcium channels mediate excitation contraction coupling in skeletal muscle
Physical coupling between voltage sensitive calcium channels and ryanodine sensitive calcium channels in sarcoplasmic particular is required to release the vesicular stores of calcium required for contraction

Answer 173

A

Calcium entry through the voltage sensitive calcium channels (VOCC/ VGCC) is required for excitation contraction
Release of calcium from vesicular stores required for contraction is mediated by calcium induced calcium release channels (CICR)
Entry of extracellular calcium may be mediated in part by the sodium calcium exchanger (NCX) working in reverse mode in the depolarised sarcolemma
In cardiac muscle calcium antagonist exert their anti-dysrhythmic action by blocking voltage sensitive calcium channels (VOCC/ VGCC)

Answer 174

A

Calcium entry through voltage gated calcium channels (VOCC/VGCC) may lead to smooth muscle contraction
Release of calcium from vesicular stores in response to activation of phospholipase C beta and production of inositol 1,4,5 triphosphate (IP3) may lead to smooth muscle contraction
M3 muscarinic receptor activation may stimulate the release of intracellular stores of calcium and smooth muscle contraction
Alpha-1 adrenoreceptor activation may stimulate the release of intracellular stores of calcium and smooth muscle contraction

Answer 175

A

Hormones - signalling between cells in different tissues via circulation

Answer 176

A

Neurotransmitters- signalling at specified cell junctions in the nervous system at synapses

Answer 177

A

Local chemical mediators- signalling between adjacent cells in the same tissue

Answer 178

A

A molecule that recognises specifically a second molecule (ligand), or family of molecules and in response to binding brings about the regulation of a cellular process.

Answer 179

A

Stimulates a biological response

Answer 180

A

Molecules that operate in the absence of a ligand

Ligand binding alone produces no response

Answer 181

A

Dihydrofolate reductase - methotrexate

Sodium channel- local anaesthetic agent, neurotoxins

Answer 182

A

Receptors are classified primarily by their specificity to a physiological signalling molecule (agonist)
They are then often divided further on the basis of their affinity to a series of antagonists.
Receptor type: acetylcholine muscarinic receptors
Agonist: muscarine
Receptor subtype: M1 M2 and M3
Antagonist: M1 (pirenzipine) M2 (gallamine) M3 (hexahydrosiladiphenol)

Answer 183

A

The affinity of ligand binding at receptor sites is generally much higher than binding of substrates to enzyme sites. This is because ligands may only be present in very small concentrations.

Answer 184

A

Binding is specific
Specificity determined by shape of binding cleft
Binding is reversible
Binding induces a conformational change and change in the activity of molecule - induced fit
No chemical modification of ligand

Answer 185

A

Any molecule that binds specifically to a receptor site
Ligand binding may produce ACTIVATION of a receptor- agonist
Ligand binding may NOT CAUSE ACTIVATION but PREVENT BINDING OF AN AGONIST = antagonist

Answer 186

A

It must produce specific receptor proteins which recognise and produce a response to the signalling molecule

Answer 187

A

Extracellular surface

Answer 188

A

Intracellular surface

Answer 189

A

Membrane bound receptors with integral ion channels
Membrane bound receptors with integral enzyme activity
Membrane bound receptors which couple to effectors through transducing proteins
Intracellular proteins

Answer 190

A

Agonist binding to ligand-gated ion channels results in a conformational change and the opening of a gated channel. The channel then permits the flow of ions down an electrochemical gradient.

Several of these receptors belong to the classical ligand-gated ion channel family, sharing similar pentameric subunit structures with four transmembrane domains E.g. Nicotinic Ach Receptors (nAchR) (gated Na+, K+, Ca2+ channels) [other examples: gamma amino butyric acid GABA (gated Cl- channels), Glycine receptor (gated Cl- channels)]

In addition to these non-classical ligand-gated ion channels can also be present. E.g. Ryanodine receptor (gated Ca2+ channels), P2x purine receptors (gated Na+/Ca2+ channels)

Answer 191

A

Agonist binding to the extracellular domain of these receptors causes a conformational change, which activates an intrinsic enzyme activity, contained within the protein structure of the receptor for example tyrosine kinase linked receptors.

E.g. Platelet Derived Growth Factor (PDGF) linked directly to Tyrosine Kinase

Tyrosine Kinase Linked Receptors autophosphorylate upon ligand binding. Phosphorylated receptor tyrosine residues are recognised either by transducing proteins, e.g. insulin receptor substrate-1 (IRS-1) or directly by enzymes containing phosphotyrosine recognition sites, Src-homology-2 (SH2) domains.
On association with receptor or transducing protein, effector enzymes become activated allosterically/by tyrosine phosphorylation by the receptor kinase. This transduces the message into an intracellular chemical event.
E.g. Insulin receptor

Answer 192

A

Seven transmembrane domain receptors (7TMDR) couple to effector molecules via a transducing molecule, a GTP-binding regulatory protein (G-Protein). This family of receptors are therefore known as G-Protein Coupled Receptors. Effectors may be enzymes (e.g. adenylyl cyclase) or ion channels (e.g. Ca2+/K+).

Many extracellular signalling molecules have a structure including seven transmembrane domains. Examples include muscarinic 2 Ach receptors (m2AchR) (K+ channel), dopamine receptors, B adrenergic adrenoreceptors (adenylyl cyclase) 5-HT receptors, light, smell and taste receptors.

Often a number of different types of G-protein receptors exist for a particular agonist, e.g. M1-5 mAchRs.

Often, separate G-protein coupled receptors will act simultaneously to both stimulate/inhibit the effector. This is Integrated Signalling, and the two inputs combine to produce a measured effect.

Answer 193

A

Hydrophobic ligands, such as the steroid hormones cortisol, oestrogen and testosterone and the thyroid hormones T3 and T4 can pass through the plasma membrane. They therefore bind to receptors inside the cell. These intracellular receptors in their resting state are bound to heat shock or chaperone proteins.

The activated receptor dissociates from the stabilising protein and translocates to the nucleus, where it binds to control regions in DNA, regulating gene expression. Compared to extracellular receptors, which act through ion channels or enzymes (see above), the action of intracellular receptors is relatively slow, as they are dependant on transcription and translation.

Answer 194

A

The concentration of many extracellular signalling molecules is very low.
With all receptor mechanisms there is a possibility of molecular amplification.
For example, by stimulating the activity of an enzyme, the binding of a chemical signal molecule to a single receptor can cause the modification of hundreds or thousands of substrate molecules. An enzymatic cascade can produce further amplification.

Answer 195

A

E.g. Cardiac Pacemaker Cells:
Noradrenaline à b1-Adrenoceptors à Increased Heart Rate
Acetylcholine à M2-Muscarinic Receptors à Slowing of Heart Rate

E.g. Hepatocytes:
Insulin à Stimulates Glycogen Synthesis from glucose
Glucagon à Stimulates Glycogen Breakdown to glucose

Answer 196

A

Pinocytosis is the invagination of the plasma membrane to form a lipid vesicle. This permits the uptake of impermeable extracellular solutes and retrieval of plasma membrane. Pinocytosis can be sub-divided into two forms, fluid-phase and receptor mediated endocytosis.

Answer 197

A

In mammals, phagocytosis is found only in specialised cells, i.e. macrophages and neutrophils. In response to the binding of a particle to receptors in the plasma membrane, the cell extends pseudopods that permit further receptor interactions and membrane invagination/particle internalisation via a ‘membrane zippering’ mechanism. Internalised phagosomes fuse with lysosomes to form phagolysosomes in which the particulate material is degraded.
This process permits the clearance of damaged cellular materials and invading organisms for destruction.

Answer 198

A

Selective internalisation of molecules into the cell by binding to specific cell receptors

Answer 199

A

Specific binding of molecules to cell surface receptors permits the selective uptake of substances into the cell.

Answer 200

A

Low Density Lipoproteins (LDL) originate in the liver and consist of a core of cholesterol molecules esterified to fatty acid, surrounded by a lipid monolayer containing phospholipids, cholesterol and a single protein species, Apoprotein B.
Animal cells that require cholesterol synthesise cell surface LDL-Receptors that recognise specifically Apoprotein B. These receptors are localised in clusters over Clathrin Coated Pits that cover approximately 2% of the cell’s surface. These pits form spontaneously, just as Clathrin spontaneously forms cages.
When LDL binds to the receptors, the pit invaginates to form coated vesicles. The vesicles are uncoated in a process that requires ATP (As they formed spontaneously) and fuse with larger, smooth vesicles called endosomes.
The pH of the endosome is lower than that of the cytoplasm (5.5-6.0), maintained by an ATP-dependent proton pump. At this pH, the LDL receptor has a low affinity for the LDL particle and the two dissociate. Because of this, the endosome is also known as the Compartment for the Uncoupling of Receptor and Ligand (CURL).
The receptors are sequestered to a domain within the endosome membrane, which buds off as a vesicle and recycles the LDL-receptor to the plasma membrane (maybe via the Golgi apparatus).
The endosomes containing the LDL fuse with lysosomes, and the cholesterol is hydrolysed from the esters and released into the cell.

Answer 201

A

Non-Functioning Receptor
If there is a mutation to the LDL binding site of the LDL-Receptor, it will prevent the binding and uptake of LDL.

Receptor Binding Normal
If the receptor binding is normal, a mutation can still lead to Hypercholesterolaemia. If there is a deletion of the C-terminal cytoplasmic domain, which prevents the interaction between the receptor and the Clathrin coat, the LDL-Receptors will be distributed over the entire cell surface instead of being concentrated in 2%.

Receptor Deficiency
A deficiency caused by a mutation that prevents expression of the LDL-Receptor.

Answer 202

A

Two Fe3+ ions bind to Apoptransferrin to form Transferrin in the circulation.
Transferrin, but not Apoptransferrin, binds to the Transferrin Receptor at neutral pH and is internalised in a similar way to LDL as described above.
Upon reaching the acidic endosome, the Fe3+ ions are released from the transferrin, but at this pH the Apoptransferrin remains associated with the transferrin receptor.
The complex is sorted in the CURL for recycling back to the plasma membrane, where at pH 7.4 the Apoptransferrin dissociates from the receptor again.

Answer 203

A

Insulin receptors only congregate over Clathrin coated pits when their agonist is bound (unlike with LDLs and iron). Insulin binding induces a conformational change in the receptor that allows it to be recognised by the pit.
In the endosome Insulin remains bound to the receptor and the complex is targeted to the lysosomes for degradation.
This mechanism allows for the reduction in the number of insulin receptors on the membrane surface, desensitising the cell to a continued presence of high circulating insulin concentration.

Answer 204

A

Some ligands that remain bound to their receptors may be transported across the cell. This is Transcytosis. Examples include maternal immunoglobulins to the foetus via the placenta and the transfer of immunoglobulin A (IgA) from the circulation to bile in the liver. During transport of IgA the receptor is cleaved, resulting in the release of immunoglobulin with a bound ‘secretory component’ derived from the receptor.

Answer 205

A

Receptors for different ligands enter the cell via the same Clathrin coated pits and the pathway from coated pits to the endosome is common for all proteins that undergo endocytosis. Different modes of this process can be defined on the basis of the destination of the internalised receptor and ligand. Receptors targeted to different cellular destinations, by short amino acid motifs, are sorted within the CURL to discrete regions of membrane, which bud off into transport vesicles

Answer 206

A

Mode 1
Fate of Receptor- recycled
Fate of Ligand- degraded
Examples- LDL 
Function- Metabolite uptake

Answer 207

A

Mode 2
Fate of Receptor- recycled
Fate of Ligand- recycled
Examples- transferrin
Function- metabolite uptake

Answer 208

A

Mode 3
Fate of Receptor- degraded
Fate of Ligand- degraded
Examples- insulin, epidermal growth factor
Function- immune complexes, receptor down regulation, removal from circulation of foreign antigen

Answer 209

A

Mode 4
Fate of Receptor- transported
Fate of Ligand- transported 
Examples-maternal IgG; IgA
Function- Transfer of large molecules across cell; E.g. Maternal immunity to foetus via placenta; E.g. Circulation to Bile

Answer 210

A

Long lasting hyperglycaemia can result in type 2 diabetes because the tissue becomes desensitised and had a reduced response to insulin as the excess production of insulin means that the enzymes are down graded, increasing the hepatic glucose production, thus contributing more to hyperglycaemia

Answer 211

A

Membrane-enveloped viruses and some toxins exploit endocytic pathways to enter cells after adventitious binding to receptors in the plasma membrane.
Once in the endosome, the acidic pH allows the viral membrane to fuse with the endosomal membrane, releasing the viral RNA into the cell where it can be translated and replicated by the host cell’s machinery to form new viral particles.
E.g. Cholera Toxin and Diphtheria toxin, both of which bind GM1 Ganglioside.

Answer 212

A

Appropriate receptors

Answer 213

A

Thyroid hormone

Steroid hormones

Answer 214

A

Transferrin
Insulin
ACTH

Answer 215

A

Ligand gated ion channels
Receptors with intrinsic enzymatic ion channels
G protein coupled (7TM) receptors

Answer 216

A

Changes in light (e.g. Rhodopsin) odours and tastes

Answer 217

A

Ions (H+, Ca2+)
Neurotransmitters (ACh, Glutamate)
Peptide and non peptide hormones (glucagon, adrenaline)
Large glycoproteins (TSH)

Answer 218

A

Single polypeptide chain (300-1200 aa’s)
7TM spanning regions
Extracellular N terminal
Intracellular C terminal

Answer 219

A

Ligand binding/ activation of GPCR
Activation of G Protein
Signalling
Termination

Answer 220

A

Two regions of GPCRs can be responsible for ligand binding:
N terminal region and other extracellular domains
Within the transmembrane domain

Answer 221

A

An activated GPCR must interact with another protein- guanine nucleotide binding protein (= G protein)
The GPCR- G protein interaction activates the G protein by causing GTP to exchange for GDP on the G protein alpha sub unit

Answer 222

A

The alpha(GTP)- betagamma complex immediately dissociates into alpha(GTP) and betagamma and each can then interact with effector proteins (second messengers) generating ion channels or enzymes

Answer 223

A

The alpha(GTP) and/or betagamma interaction with effectors lasts until the alpha subunit GTPase activity hydrolyses GTP back into GDP 
Alpha(GDP) and betagamma then reform an inactive heterotetrameric complex

Answer 224

A

GTPase is integral to alpha subunit

Answer 225

A

Activated GPCRs preferentially interact with specific types of G protein. The G (alpha) subunit is a primary determinant.
In turn G(alpha) subunits and G(beta gamma) subunits interact with specific effector proteins
In this way an extracellular signalling molecule working by a specific GPCR activate a single, or a small sub population of G proteins and effectors in the cell to bring about a specific cellular response.

Answer 226

A

Adrenaline, noradrenaline
G(alpha)s, G(betagamma)
Stimulates adenylyl cyclase
glycogenolysis, lipolysis

Answer 227

A

Adrenaline, noradrenaline
G(alpha)i, G(betagamma)
Inhibits adenylyl cyclase

Answer 228

A

Adrenaline, noradrenaline
G(alpha)q, G(betagamma)
Stimulates Phospholipase C
Stimulates smooth muscle contraction

Answer 229

A

Light
G(alpha)t, transducin
Stimulates cyclic GMP phosphodiesterase
Visual excitation

Answer 230

A

Acetylcholine
G(alpha)i, G(betagamma)
Inhibits adenylyl cyclase, stimulates K+ channels
Slowing of cardiac pacemaker

Answer 231

A

Acetylcholine
G(alpha)q, G (betagamma)
Stimulates Phospholipase C

Answer 232

A

Adenylyl cyclase ATP–> cyclic AMP
Phospholipase C PIP2 –> IP3 + DAG
Phosphoinositide-3-kinase (PI3K) PIP2–> PIP3
cGMP Phosphodiesterase cyclic GMP –> 5’GMP

Answer 233

A

Voltage gated Ca2+ channels

G protein regulated inwardly rectifying K+ channels (GIRKs)

Answer 234

A

(Noradrenaline, dopamine) Agonist binds to GPCR (beta-adrenoreceptors, D1 dopamine receptors, H2 histamine receptors) stimulating Gs protein
G protein splits into alpha-GTP and betagamma
Alpha-GTP stimulates ADENYLYL CYCLASE
Stimulates ATP to cAMP conversion.
cAMP activates cAMP dependent protein kinase (PKA), Epacs- guanine nucleotide exchange factors, Cyclic nucleotide gated ion channel
Causes increased glycogenolysis and gluconeogenesis in the liver, increased lipolysis in adipose tissue, relaxation of a variety of types of smooth muscle and positive inotropic and chronotropic effects in the heart.

Answer 235

A

(Noradrenaline, dopamine) Antagonist binds to GPCR (alpha2-adrenoreceptors, D2 dopamine receptors, mu-opoid receptors) stimulating Gi protein
G protein splits into alpha-GTP and betagamma
Alpha-GTP inhibits ADENYLYL CYCLASE
Inhibits ATP to cAMP conversion.
cAMP no longer activates cAMP dependent protein kinase (PKA), Epacs- guanine nucleotide exchange factors, Cyclic nucleotide gated ion channel

Answer 236

A

Through cAMP dependent protein kinase (PKA)

Answer 237

A

cAMP dependent kinase is made up of 2 regulatory subunits and 2 catalytic subunits
The 2 R subunits rest in the C site preventing their action
Binding of 2 cAMPs per R subunit causes the release of the C subunits which are thus free to act as protein kinases and add phosphates to aa residues (serine and threonine) on proteins
Phosphorylation is a critical way for the cell to send out instructions

Answer 238

A

Agonist binds to the GPCR (alpha1- adrenoreceptors, M1 muscarinic receptors, H1histamine receptors) stimulating Gq protein
G protein splits into alpha(GTP) and betagamma
Alpha(GTP) activates Phospholipase C
Phospholipase C catalyses the cleavage of membrane phospholipid (PIP2) into 2 second messengers- IP3(hydrophilic) and DAG(lipophilic)
IP3 stimulates release of calcium from endoplasmic reticulum via IP3 proteins
Increase in calcium in the cell and DAG activates Protein kinase C causing phosphorylation

Answer 239

A

Key feature of many cell signalling pathways
E.g.- a few molecules of adrenaline binding to the cell surface B adrenoreceptors may cause a relatively massive cellular response.
The B-adrenoreceptor–> Gs protein–> adenylyl cyclase part of the cascade causes relatively little amplification- never the less activation of adenylyl cyclase generates many molecules of cyclic
AMP which then activate the enzyme PKA.

Answer 240

A

Cyclic GMP Phosphodiesterase is a specialised mechanism found in the photoreceptive cells of the retina. It regulates the breakdown of the second messenger cyclic GMP phosphodiesterase by Gt (Transducin).
Light sensing protein rhodopsin activates Gt which activates cGMP phosphodiesterase enzyme to hydrolyse cyclic GMP to 5’GMP

Answer 241

A

Once a receptor has productively interacted with a G-Protein, the binding of the agonist is weakened and agonist-receptor dissociation is likely to occur.
Whilst activated, the receptor is susceptible to a variety of protein kinases that phosphorylate the receptor and prevent it activating further G-Proteins. This comprises an important part of the receptor desensitisation phenomenon observed for most G-Protein-Coupled Receptors.
The active lifetime of a-GTP may be limited by cellular factors that stimulate the intrinsic GTPase activity of the Ga subunit.
Enzymatic activities in the cell are such that the basal state is favoured. Therefore cells contain high activity enzymes that metabolise second messengers, rapidly returning their levels to the basal.
Enzymatic cascades activated downstream of second messenger/protein kinase activation act to oppose their effect.

Answer 242

A

The rate at which the sinoatrial node fires an action potential can be affected by Ach release by the parasympathetic nerves.
The predominant receptor type is M2 muscarinic cholinoceptors and activation of these increases the open probability of K+ channels via Gi.
Increase plasma membrane permeability to K+ causes hyperpolarisation, slowing the intrinsic firing rate, resulting in a negative chronotropic effect.

Answer 243

A

Sympathetic innervation of the cardiac ventricles (and/or circulating adrenaline) can influence the force of contraction (inotropy).
Activation of B-Adrenoceptors (predominantly B1), increases the open probability of voltage operated calcium channels (VOCCs) via Gs.
Gs both interact directly with the VOCCs, and indirectly via cyclic AMP –> PKA –> Phosphorylation and activation of VOCCs.
The influx of Ca2+ brings about a positive inotropic effect.

Answer 244

A

Noradrenaline –> alpha1-adrenoceptors (vasculature smooth muscle cells)–> Gq –> Phospholipase C –> IP3 (and DAG)–> Release of Ca2+ from ER –> Rise in Ca2+ and DAG activates protein kinase C pathways –> vasoconstriction

Answer 245

A

(CNS and PNS) Pre-synaptic G-Protein-Coupled Receptors can influence Neurotransmitter release. For example, pre-synaptic mu-opiod receptors can be stimulated, either by endogenous opiods or by analgesics such as morphine to couple to GaI proteins.

Morphine –> (mu-opoid) GPCR –> Gi protein –> alpha GTP and betagamma –> betagamma causes a decrease in VOCC activity and decrease in calcium influx and neurotransmitter release

Answer 246

A

ACh –> M3 muscarinic receptor (bronchiole smooth muscle cells)–> Gq –> Phospholipase C –> IP3 (and DAG)–> Release of Ca2+ from ER –> Rise in Ca2+ and DAG activates protein kinase C pathways –> bronchoconstriction

Answer 247

A

Diverse range of stimuli, receptors, G proteins and effectors

Answer 248

A

Specific ligand receptor interactions, specific G protein alpha subunits (betagamma) recruited which are coupled to particular effector pathways

Answer 249

A

For an extracellular stimulus (which may amount to only a few molecules of a hormone interacting with appropriate cell surface receptors) to generate an intracellular response, amplification of the signal is essential. Therefore an important role of the receptor-G protein-effector signalling system is to allow such amplification to occur. Amplification of the initial signal can be achieved at a number of levels:

Activated receptor can cause (sequential) GTP/GDP exchange on more than one G protein
An activated G alpha-GTP/free Gβγ can activate multiple effector molecules
Effector molecules act catalytically. Thus, activation of adenylyl cyclase by alpha s-GTP results in conversion of 100-1000s of molecules of ATP to cyclic AMP. Similarly, the opening of an ion channel by alpha-GTP allows 100-1000s of ions to move across the plasma membrane.

Answer 250

A

Currently 40 % of all available prescription drugs exert their therapeutic effects directly (as agonists or antagonists) or indirectly at GPCRs

Answer 251

A

Binds to the receptor and activates it (leading to intracellular signal transduction events)

Antiasthma- B2 adrenoreceptor agonists= bronchodilation- SALBUTAMOL, SALMETEROL
Analgesia/ anaesthesia - mu-opiod receptor agonists= modulation betagamma, decrease in VOCC and decreased Ca2+ influxe- MORPHINE, FENTANYL

Answer 252

A

Bind to the receptor but do not activate it (block the effects of agonists at the receptor)

cardiovascular (e.g. Hypertension) - B adrenoreceptor antagonists- PROPRANOLOL, ATENOLOL
neuroleptics (e.g. antischizophrenic) - D2 dopamine receptor antagonists- HALOPERIDOL, SULPIRIDE

Answer 253

A

Nephrogenic diabetes insipidus can be caused by a loss of function mutation to the V2 vasopressin receptor

Retinitis pigmentosa can be caused by a loss of function mutation to rhodopsin

Answer 254

A

Familial male precocious puberty is caused b a gain of function mutation to the Luteinising hormone (LH) receptor

Answer 255

A

Toxin complexes bind to the cell and an enzyme is injected into the cell
Both toxins (cholera and pertussis) are important experimental tools used to study GPCR- G protein signalling 
Cholera and pertussis toxins are enzymes that ADP-ribosylate specific G proteins

Answer 256

A

CTx eliminates GTPase activity of G(alpha)s
G(alpha)s becomes irreversibly activated
ADP RIBOSYLATION of G(alpha)s by CTx prevents the de activation of Gs protein mediated signalling

Answer 257

A

PTx interferes with GDP/GTP exchange on G(alpha)i
G(alpha)i becomes irreversibly inactivated
ADP RIBOSYLATION of G(alpha)i by PTx prevents Gi protein activation by GPCRs

Answer 258

A

By binding to a target (most of the time reversibly)

Binding governed by association and dissociation rates

Answer 259

A

Proteins

There are some exceptions – some antimicrobial and antitumour drugs fbnd DNA

Answer 260

A

Enzymes
GPCRs
Ion channels
Transporters
Nuclear hormone receptors 
Other receptors
Integrins
Miscellaneous

Answer 261

A

The concentration of drug molecules around receptors is critical in determining drug action
Drugs of equivalent molar concentrations have the same concentration of drug molecules
Drugs of the equivalent concentrations by weight may not have the same concentration of drug molecules

Answer 262

A

6 x 10 ^23

Answer 263

A

1mole in 1litre

Answer 264

A

Molarity = grams/litre divided by molecular weight

Answer 265

A

The likelihood of a ligand binding to its target

Answer 266

A

The likelihood of activation of the receptor and a response (taking into account cell and tissue components e.g number of receptors)

Answer 267

A

The likelihood of activation of the receptor

Answer 268

A

Drugs that bind to receptors and cause a response – have affinity and efficacy

Answer 269

A

Drugs that bind to receptors but don’t cause response – they have affinity only

Answer 270

A

Information is often obtained by binding of a radioligand (radio active version of the ligand)
Affinity can be determined by means other than radioligand binding

Answer 271

A

Proportion of bound receptors versus concentration of drug in logarithmic terms

Answer 272

A

Rectangular hyperbole

Answer 273

A

Sigmoidal

Answer 274

A

The maximum binding capacity

Tells us about the total number of receptors

Answer 275

A

Measure of affinity; concentration of drug needed for 50% occupancy

Answer 276

A

High affinity (because a lower concentration of drug is required to occupy 50% of the receptors)

Answer 277

A

Low affinity (because a higher concentration of drug is required to occupy 50% of the receptors)

Answer 278

A

Rectangular hyperbole

Answer 279

A

Sigmoidal

Answer 280

A

A change in the signalling pathway

A change in cell /tissue behaviour (e.g.contraction)

Answer 281

A

Where we have a known concentration of drug at the site of action
Using measuring a response and cells/tissues

Answer 282

A

Where the concentration at the site of action is unknown

Used when measuring response in a whole animal

Answer 283

A

The maximum response

Answer 284

A

Effective concentration giving 50% of the maximum response; a measure of potency (dependent on intrinsic efficacy and affinity and number of receptors and efficacy)

Answer 285

A

Efficacy is measured in relative terms, with no absolute scale.
Agonists with different E max values have different efficacy.
However agonists with the same E max values may not have identical efficacy
The two drugs MAY DIFFER IN AFFINITY, meaning that the relationship between the occupancy and response will be different for the two agonists – one may be more able to convert binding into function
Efficacy cannot be determined without knowing affinity

Answer 286

A

Reversible airflow obstruction and from here plasm
Treatment goal is to activate B2 adrenoreceptors (GPCR) to relax airways
But there are B adrenoreceptors elsewhere in the body (e.g. B1 in the heart) - increase the rate and force of contraction (angina)
Salbutamol- Kd B1 20 micromolar B2 1 micromolar (low affinity (in comparison to salmeterol e.g.) but utility is enhanced by B2 selective efficacy and route of administration)
Salmeterol- Kd B1 1900nM B2 0.55nM (high affinity; no selective efficacy- selectivity based on high affinity)

Answer 287

A

Affinity: does it bind?
Efficacy: does it do what it supposed to do?
Selectivity – off target effects?
Drug metabolism/pharmacokinetics – how does the body deal with it?
Physiochemical properties – solubility, pH, stability, crystallinity

Answer 288

A

In some cases less than 100% receptor occupancy will give 100% response
EC50 < Kd (50% of the maximal response takes less than 50% of receptor occupancy)
The relationship between receptor occupancy and response is non-linear and influenced by amplification in the signal transduction pathway and the fact that the response is limited by postreceptor event/properties of the tissue
Some tissues have more receptors than required to produce a maximum response. They have spare receptors or a receptor reserve.
Spare receptors increase sensitivity – allowing a response at low concentrations of agonist

Answer 289

A

Changing receptor number changes agonist potency and can affect the maximum response

Answer 290

A

When comparing the ability of different agonists to evoke responses in tissues, it is sometimes observed that some drugs cannot produce a maximal effect, even with full receptor occupancy. These drugs are referred to as partial agonists

Answer 291

A

EC50 (measure of potency) = Kd (measure of affinity) for a partial agonist
The potency of a drug is dependent on both its affinity and efficacy; therefore partial agonists can be more or less potent than full agonists

Answer 292

A

Binding to target, preventing the binding of the full agonist to the target

Answer 293

A

Increasing receptor number can change a partial agonist into a full agonist
The partial agonist still has low intrinsic efficacy at each receptor BUT there are sufficient receptors to contribute to a a full response

(E.g. Partial agonists may each bind to LOTS of targets and activate them a little bit (low efficacy); all the activated receptors accumulate to give a FULL response)

Answer 294

A

Maximal response indicates intrinsic activity (on a conc response graph)
Partial agonist have lower efficacies than full agonists but full agonists with identical intrinsic activities may have different efficacies

Answer 295

A

Opioids are used for pain relief and recreationally (heroin) – but can cause respiratory depression and DEATH
They act through mu- opioid receptors (GPCRs)
Morphine is a full agonist of the receptor- used for pain relief
Buprenorphine is a partial agonist, with a higher affinity but lower efficacy than morphine
- Can be advantageous if it provides adequate pain control, as there is less respiratory depression
- Used in gradual withdrawal from overuse of opioids
*example of a partial agonist acting as an antagonist of a full agonist

Answer 296

A

Block the effects of agonists
Prevent receptor activation by agonists
Affinity not efficacy

Answer 297

A

Reversible competitive antagonism
Irreversible competitive antagonism
Non-competitive antagonism

Answer 298

A

Commonest and most importantly therapeutics
Competitive antagonists compete with agonists for binding
Inhibition is surmountable- still get full biological response
Adding more agonist makes it harder antagonist to compete
IC50 = concentration of antagonist giving 50% of the inhibition response = index of antagonist potency *
*(determined by strength of agonist)
Kd is used to describe antagonist affinity

Answer 299

A

Causes a parallel shift to the right of the agonist concentration response curve

Answer 300

A

Naloxone- high affinity for mu opioid receptors

* Reversal of opioid mediated respiratory depression

Answer 301

A

Causes a parallel shift to the right of the agonist- concentration response curve at higher concentrations suppress the maximal response

Answer 302

A

Phenoxybenzamine- binds to alpha 1 adrenoreceptors
* Hypertension episodes in pheochromocytoma

-> tumour of adrenal chromaffin cells
-> excessive adrenaline/ NA
/(Phenoxybenzamine)-> vasoconstriction (alpha 1 adrenoreceptors)

Answer 303

A

Antagonist binds to other allosteric sites
Provides binding site for: agonists and molecules that enhance or reduce effects of agonists (no competition of the binding site but affects orthosteric ligand affinity or efficacy)

Answer 304

A

NMDA receptor
Glutamate site and ketamine site (antagonist does not competed with glutamate site but with the ketamine site- it lowers the ionic flow
Analgesia- reduced central excitation

Answer 305

A

Antagonist dissociates slowly or not at all
With increased concentration of antagonist or increased time more receptors are blocked by the antagonist- non surmountable- can’t get full biological response back

Answer 306

A

What the body does to a drug

Answer 307

A

Pharmaceutical process – is the drug getting into the patient?
Pharmacokinetic process – is the drug getting into the site of action?
Pharmacodynamic process – is the drug producing the desired pharmacological effect?
Therapeutic effect – is the pharmacological effect translated into a therapeutic effect?

Answer 308

A

Absorption
Distribution
Metabolism
Elimination

Answer 309

A

Solid (tablet) or liquid – if it’s solid, solubility and acid stability in stomach must be considered; rate of action depends on dissolution

Answer 310

A

Focal – eye, skin, inhalation
Systemic – enteral – sublingual, oral, rectal; parenteral – subcutaneous, intramuscular, intravenous, inhalation, transdermal

Answer 311

A

Proportion of a drug given orally (or other routes except intravenously) that reaches the circulation unchanged
Can be expressed as: amount – depends on GI absorption (food/disease) and first pass effect– Measured by area under curve of blood drug level versus time plot
Can be expressed as: rate – depends on pharmaceutical factors and rate of gut absorption – measured by peak height and rate of rise of drug levels in the blood

Answer 312

A

100 x (AUC oral/ AUC injected)

Answer 313

A

Tells us about the safety of the drug

Allows us to maximise the time that the drug is in the therapeutic window

Answer 314

A

Maximum tolerated dose/minimum effective dose
LD 50/ED 50
Lethal dose to 50% of people/ Effective dose to 50% of people

Answer 315

A

Desired therapeutic effect and unwanted adverse effect

Answer 316

A

Less safe

Answer 317

A

More safe

Answer 318

A

Drugs administered intravenously enter directly into the systemic circulation and have direct access to the rest of the body
FPM- Drugs administered orally are first exposed to the liver via the portal system and may be extensively metabolised before reaching the rest the body (systemic circulation)- lignocaine, opiates, propranolol, glyceryl trinitrate

Answer 319

A

Parenteral route- IV, SC, IM
Rectal route- drainage to portal and systemic system
Sublingual route- glyceryl trinitrate in angina (GTN spray)

Answer 320

A

Theoretical volume into which the drug has distributed assuming that this occurs instantaneously (calculated as amount given/plasma concentration at T =0)
Obtained by extrapolation of plasma levels at zero time
Tells us about solubility of drugs

Answer 321

A

The drug is lipid soluble

Answer 322

A

The drug is water soluble

Answer 323

A

Amount of free drug determines the drug actions at receptors- not the total level
Displacement of drugs from binding sites causes protein binding drug interactions (class II drugs free up class 1 drugs from binding sites allowing them to ACT ON RECEPTORS or BE ELIMINATED)
Protein binding interactions are important when the OBJECT DRUG (class I) - is highly bound to albumin, has a small volume of distribution (water soluble) and has a low therapeutic ratio (not very safe) because administration of a PRECIPITANT DRUG (Class II) frees up the object drug to allow it to have its action or be eliminated
Object drug (Class I) - is used at a dose which is much lower than the number of albumin binding sites
Precipitant drugs (Class II) - is used at a dose which is much greater than the number of available albumin binding sites (and will displace class I drugs from binding sites)
Binding interactions are TRANSIENT/ TEMPORARY - although free drug levels rise (greater effects at receptors)- elimination rate will also rise (since this depends on free drug levels); steady state is restored quickly in a few days

*bear in mind though that when a patient is taking the object drug, taking a supplementary precipitant drug will temporarily lead to higher free levels of the object drug and hence there is a higher risk of toxicity.

Answer 324

A

1- warfarin- sulphonamides, aspirin, phenytoin
2- tolbatamide- sulphonamides, aspirin
3- phenytoin- valproate

Answer 325

A

If drugs are metabolised by enzymes that obey the Michaelis Menten kinetics then:
Rate of metabolism/ elimination = Vmax [C] / Km + [C]
Can be zero or first order kinetics

Answer 326

A

Rate of elimination is directly proportional to the drug level
Constant fraction of drug is eliminated in unit time
Half life can be defined - as the rate of decline of plasma drug level is directly proportional to drug level
[C] < Km –> rate of metabolism = Vmax[C]/Km
Gives a predictable therapeutic response from dose increases (most drugs behave this way)
Straight line- logs

Answer 327

A

Rate of elimination is a constant
[C] > Km –> rate of metabolism = Vmax[C]/[C] = Vmax
So enzyme is saturated
Therapeutic response can suddenly escalate as elimination mechanisms saturate
Straight line- not logs

Answer 328

A

Rate of drug metabolism vs dose of a drug
At low doses drug metabolism is first order, that is proportional to drug dose
At high dose, drug metabolism is zero order = constant and independent of drug dose

Answer 329

A

A steady state will be reached within 5 half lives, irrespective of dose or frequency of administration

Answer 330

A

If an immediate effect is necessary
If a half life is long
- often determined by volume of distribution

Answer 331

A

Metabolism by the liver

Excretion by the kidney

Answer 332

A

Phase I- reactive group exposed/ added to stable/ unreactive drug (prodrug); oxidation, reduction, hydrolysis; cytochrome P450 enzyme system; NADPH; enzymes are inducible or inhibitable
Phase II- conjugation with a polar molecule = water soluble complex; glucuronic acid, glutathione, sulphate ions; specific enzymes & UDPGA

Answer 333

A

Phenobarbitone- warfarin, phenytoin
Rifampcin- oral contraceptive
Cigarettes- theophylline

Answer 334

A

Cimetidine- warfarin, diazepam

Answer 335

A

Drugs have a low therapeutic ratio
Drug is being used at the minimum effective concentration
Drug metabolism follows zero order kinetics

Answer 336

A

Free unbound drug enter the glomerular filtrate
There is active secretion of other drugs in the proximal tubule
In the distal tubule there is reabsorption of the lipid soluble unionised drug (passes membrane easily) to be recirculated in the blood- dependent on pH
Ionised lipid insoluble drug is passed into the urine

pK = pH at which half of the drug is ionised and half of it is unionised

Answer 337

A

Unionised/ uncharged lipid soluble drugs can pass the membrane more easily
For weak acids (e.g. aspirin), making the urine alkaline will make the drug ionised, so there will be less tubular absorption because the charged drug stays in the tubule lumen.
For weak bases (e.g. amphetamine), making the urine acidic will make the drug ionised, so there will be less tubular absorption because the charged drug stays in the tubule lumen.

Answer 338

A

In renal disease,
1. If the drug or active metabolite is excreted as its main route of elimination, T1⁄2 is prolonged. Therefore, lower the maintenance
dose.
2. It takes 5 T1⁄2s to reach a new equilibrium every time you change the dose.
3. The loading dose is unchanged, unless volume of distribution changes (e.g. digoxin)
4. Protein binding of drugs is altered

Answer 339

A

Alcohol- inhibits metabolism
Aspirin, sulphonamides, phenytoin- displacement from plasma proteins
Broad spectrum antibiotics- reduced vitamin K synthesis by gut
Aspirin- reduced platelet function

Answer 340

A

Barbiturates, rifampicin- Induces liver metabolizing enzymes

Answer 341

A

In liver disease, be careful with drugs with a low therapeutic ratio.
Cellular dysfunction- warfarin, phenytoin, theophylline
Portasystemic shunts- opiates, propranolol
Reduced blood flow- opiates, propranolol, lignocaine
Reduced albumin- affects drug binding to plasma protein

Answer 342

A

Amphipathic molecules form one of two structures in water, micelles and bilayers. Bilayer formation is spontaneous in water and is driven by the van der Walls forces between the hydrophobic tails.
Co-operative structure is stabilised by non-covalent forces; electrostatic and hydrogen bonding between hydrophilic moieties and interactions between hydrophilic groups and water.

Answer 343

A

All or nothing- only occur if they reach a threshold
Distinct signals- due to inactivation of Na+ channels and Hyperpolarisation in RRP
Propagated without loss of amplitude- local current theory, length constant, previous region in hyperpolarised state

Answer 344

A

Length constant- distance its takes for the potential to fall to 37% of its original value
The further the local current spreads the faster the conduction velocity of the axon

Answer 345

A

Controls involuntary functions
Controls all efferent outputs of the body, except innervation of skeletal muscle - somatic efferent nervous system
Regulated by afferent inputs
SNS and PNS
Tissues are not always innervated by both branches but where they are SNS and PNS may have opposing effects- notable exceptions= ANS control of salivary secretions

Answer 346

A

Stressful situations, fight or flight
Thoraco-lumbar outflow (lateral horn of grey matter in the spinal cord)
Short myelinated preganglionic neurone
nAchR (ligand gated ion channel) - sympathetic chain
Long unmyelinated postganglionic neurone
NA alpha1,2 and beta 1,2 (GPCR)

Answer 347

A

Sweat glands- nAchR and mAchR

Adrenal glands- nAchR and chromaffin cells –> adrenaline into BLOOD

Answer 348

A

Atria/ ventricles
SAN- tachycardia
Ventricles- positive inotropy

Answer 349

A

Vasculature- arteriolar venous contraction
Lungs/ GI/ GU tract- bronchiolar, intestinal, uterine relaxation
GU tract- bladder spinchters contraction
Eye- radial muscle contraction

Answer 350

A

Salivary- increased viscous secretion

Answer 351

A

Renin release

Answer 352

A

Basal activities, rest and digest, basal heart rate
Cranial sacral outflow (lateral horn of grey matter in medulla and spinal cord)
Long myelinated preganglionic neurone
nAChR (ligand gated ion channel)
Short unmyelinated post ganglionic neurone
mAchR (GPCR)

Answer 353

A

SAN- bradycardia

AVN- reduced cardiac conduction velocity

Answer 354

A

Lungs- bronchiole, bronchiolar contraction
GI tract- increased intestinal mobility/ secretion
GU tract- bladder contraction/ relaxation and penile erection
Eye- ciliary muscle and iris spinchter contraction

Answer 355

A

Increased sweat/ salivary/ lacrimal secretion

Answer 356

A

Catecholamines disorders- pheochromocytoma, baroreflex failure
Central autonomic disorders- multiple system atrophy (MSA)- autonomic dominated
Orthostatic intolerance syndrome
Paroxysmal autonomic syncopes
Peripheral autonomic disorders - Guillain Barré syndrome - familial dysautonomia

Answer 357

A

Hereditary sensory and autonomic neuropathy (HSAN) type III
Autosomal recessive
Defective gene encodes IkB kinase complex associated protein affecting development and survival of sensory sympathetic and some parasympathetic neurons
Almost exclusively seen in children of Ashkenazi Jewish descent (1/3700 live births in Israel carry a mutant gene)
FD infants normally present because of feeding/ swallowing difficulties
FD symptoms include- dysautonomic crises, GI tract dyscoordination, cardiovascular and respiratory dysfunction, altered sensory perception, spinal curvature

Answer 358

A

Acetylcholine is synthesized by the enzyme choline acetyltransferase from choline (an essential dietary constituent) and the metabolic intermediate acetyl CoA in the cytoplasm of cholinergic terminals. Although some of the ACh is degraded by cytoplasmic cholinesterase, the majority is transported into synaptic vesicles by an indirect active transport mechanism similar to that described above for noradrenaline. Cholinergic terminals possess numerous vesicles containing high concentrations (>100 mM) of ACh that can be released by Ca2+-mediated exocytosis.
Released ACh can interact with both pre- and post-synaptic cholinoceptors. However, the opportunity to interact with receptors is limited by ACh in the synaptic cleft being acted upon by cholinesterase, which rapidly degrades ACh to choline and acetate. The activity of this enzyme is higher at fast (nicotinic) cholinergic synapses limiting the synaptic cleft half-life of ACh to a few milliseconds. Most choline is recaptured by a choline transporter present in the synaptic terminal.

Answer 359

A

ay have a preferential ganglion (e.g. trimethaphan) or neuromuscular (e.g. tubocurarine, pancuronium) blocking action. The former class of agent is rarely used clinically, whilst the latter are used to cause muscle paralysis during anaesthesia.

Answer 360

A

Muscarinic cholinoceptor agonists vary in their muscarinic/nicotinic selectivity and resistance to degradation by cholinesterase. Note that no agent shows significant selectivity between muscarinic receptor subtypes (i.e. M1, M2, M3 selectivity). The major clinical use is in the treatment of glaucoma (raised intraocular pressure) where the agent (usually pilocarpine) can be applied in the form of eye drops. Minor uses include suppression of atrial tachycardia, increasing gastrointestinal activity after abdominal surgery, and stimulation of bladder emptying.

Answer 361

A

Muscarinic cholinoceptor antagonists show little selectivity for receptor subtypes, but vary in their peripheral versus central actions. Hyoscine (methylscopolamine) was used as anaesthetic premedication as it decreases bronchial and salivary secretions, prevents reflex bronchoconstriction, reduces any bradycardia induced by the anaesthetic and also has a sedative effect. Local application of a poorly absorbed muscarinic cholinoceptor antagonist (e.g. ipratropium bromide) can be used to treat bronchoconstriction in asthmatics where the constriction is caused by increased parasympathetic discharge. Pupillary dilatation and paralysis of accommodation can be caused by muscarinic cholinoceptor antagonists (e.g. homatropine, tropicamide) facilitating opthalmoscopic examination and having a beneficial effect in various (rare) eye conditions.

Answer 362

A

Cholinesterase inhibitors (e.g. edrophonium, physostigimine, dyflos) differ in their longevity of action and their peripheral versus central effects. They are used to acutely reverse the effects of non-depolarizing neuromuscular blocking agents used in anaesthesia, in the topical treatment of glaucoma and in the treatment of myasthenia gravis. Recently, cholinesterase inhibitors (e.g. tacrine, donepezil) have been introduced for the treatment of the early stages of Alzheimer’s disease.

Answer 363

A

Noradrenaline (and the other signalling molecules dopamine and adrenaline) is synthesized from tyrosine within the nerve terminal (see diagram below). The rate-limiting enzyme is tyrosine hydroxylase. The presence of phenylethanolamine N-methyltransferase in the chromaffin cells of the adrenal medulla allows adrenaline to be synthesized as the main product for release. The enzyme dopamine B-hydroxylase is located within synaptic vesicles and therefore newly synthesized dopamine is transported into the vesicle prior to conversion to noradrenaline. The vesicular transporter recognizes not only dopamine, but also noradrenaline allowing noradrenaline to be recycled following release and re-uptake (see below). Under most circumstances the cytoplasmic noradrenaline concentration is low, whilst the intravesicular concentration is very high (0.5-1.0 M), this is possible because the vesicular transporter exploits a H+- ATPase-generated cytoplasm:vesicle H+-gradient to move catecholamines against their concentration gradient. Cytoplasmic noradrenaline is susceptible to enzymic breakdown by monoamine oxidase (MAO)
Noradrenaline release is triggered by depolarization of the nerve terminal membrane, Ca2+-entry and fusion of vesicles with the pre-synaptic plasma membrane (Ca2+-mediated exocytosis). Released noradrenaline can interact with both pre-and post-synaptic adrenoceptors. However, the opportunity to interact with receptors is limited by a high affinity reuptake system (called “Uptake 1”) which acts to rapidly remove noradrenaline from the synaptic cleft, rapidly decreasing the localized concentration increase following release and thus terminating its actions. Any noradrenaline escaping from the synaptic cleft is removed from the extracellular space by another, widespread, lower affinity re-uptake system (“Uptake 2”). Noradrenaline recaptured by the nerve terminal has two fates: it can be re-vesiculated and therefore undergo further release/ reuptake cycles or it can be metabolized (initially by MAO).

Answer 364

A

Alpha-Methyl-tyrosine competitively inhibits tyrosine hydroxylase and, therefore, blocks de novo synthesis of noradrenaline. Only clinical use is to inhibit noradrenaline synthesis in pheochromocytoma (noradrenaline-secreting tumour).

Answer 365

A

Alpha-Methyl-DOPA is taken up by adrenergic neurones and is converted to alpha-methyl- noradrenaline by the sequential action of DOPA decarboxylase and dopamine beta-hydroxylase. Unlike the true neurotransmitter, alpha-methyl- noradrenaline is poorly metabolized and therefore accumulates in the synaptic vesicles of noradrenergic terminals. It is released by Ca2+- mediated exocytosis, but differs from noradrenaline in that it preferentially activates pre-synaptic alpha2-adrenoceptors reducing transmitter release. The ability of α-methyl-DOPA to form the “false transmitter” alpha-methyl- noradrenaline has been exploited in the treatment of hypertension.

Answer 366

A

CarbiDOPA inhibits DOPA decarboxylase in the periphery, but not in the CNS (because it does not cross the blood-brain-barrier). It is used in combination with L- DOPA in the treatment of Parkinson’s disease (a dopamine deficiency in the basal ganglia).

Answer 367

A

Adrenergic blocking drugs (e.g. guanethidine, bretylium) are selectively concentrated in terminals by Uptake 1. They act via a variety of mechanisms, including a local anaesthetic action reducing impulse conduction and Ca2+-mediated exocytosis, a partial blocking action on reuptake of neurotransmitter, and
depletion of noradrenaline from synaptic vesicles. They are now rarely used therapeutically, because of severe side-effects (postural hypotension).

Answer 368

A

Indirectly-acting sympathomimetic agents (IASAs)(e.g. tyramine, amphetamine, ephedrine) are structurally related to noradrenaline. Because they are only weak agonists at adrenoceptors they are thought to exert their actions by other/additional mechanisms. IASAs are recognised and transported into the adrenergic terminal by Uptake 1 and are taken up into synaptic vesicles where they cause noradrenaline to leak from the vesicle. The displaced noradrenaline can leak into the synaptic cleft by a mechanism unrelated to Ca2+-mediated exocytosis. The extent to which noradrenaline leaks into the synaptic cleft can be greatly enhanced by inhibition of the noradrenaline-degrading enzyme MAO.

Answer 369

A

Uptake 1 inhibitors comprise an important class of therapeutic agents - the tricyclic antidepressants (e.g. amitriptyline) - however, these agents exert their therapeutic actions centrally and their possible peripheral actions (enhancement of sympathetic actions to cause, e.g. tachycardia and cardiac dysrhythmias) are unwanted side-effects avoided by choice of drug and dose.

Answer 370

A

Adrenoceptor agonist pharmacology has produced highly receptor subtype-selective agents, therefore a knowledge of the pre- and post- synaptic adrenoceptor subtype disposition may allow the rational use of adrenoceptor agonists to achieve specific therapeutic ends. Important uses of adrenoceptor agonists are given below:
 Selective beta 1-agonists (e.g. dobutamine) can cause positive inotropic and chronotropic effects which may be useful in treating circulatory shock - however, all beta 1-agonists are prone to causing cardiac dysrhythmias
 Selective beta 2-agonists (e.g. salbutamol, terbutaline) are highly effective in reversing bronchconstriction in asthmatics
 Selective alpha 1-agonists (e.g. phenylephrine, oxymetazoline) are used as nasal decongestants. Alpha 1-agonists (though more usually adrenaline) may be given in conjunction with a local anaesthetic injection to cause local vasoconstriction and so retard the dissipation of the anaesthetic.
 Selective alpha 2-agonists (e.g. clonidine) can be used as anti- hypertensive agents. This action is brought about partly through stimulation of inhibitory pre-synaptic receptors which decrease noradrenaline release and partly through a centrally-mediated action

Answer 371

A

Adrenoceptor antagonists are also widely used therapeutically. Most useful drugs are alpha or beta- adrenoceptor-selective and increasingly drugs which distinguish alpha and beta- subtypes are being used to reduce the unwanted side-effect profiles associated with therapy. Important uses of adrenoceptor antagonists are given below:
 alpha-adrenoceptor antagonists (e.g. phentolamine, and the irreversible blocker phenoxybenzamine) are used to cause peripheral vasodilatation (i.e. oppose sympathetically-mediated vasoconstriction) in the treatment of peripheral vascular disease. They are not used to treat hypertension because they cause postural hypotension and reflex tachycardia.
 Selective alpha 1-adrenoceptor antagonists (e.g. prazosin) are used in the treatment of hypertension, although postural hypotension and impotence are still common unwanted side-effects.
 beta-adrenoceptor antagonists (e.g. propranolol) or beta 1-adrenoceptor antagonists (e.g. atenolol) are used to treat hypertension, cardiac dysrhythmias, angina and myocardial infarction. Possible unwanted side-effects include bronchoconstriction (particularly using non-selective β-adrenoceptor antagonists in patients susceptible to parasympathetically-mediated brochospasm), bradycardia, cold extremities, insomnia and depression. Some trials report that the use of partial agonists (e.g. alprenolol, oxprenolol) cause fewer side-effects as they provide a low tonic stimulation of beta -adrenoceptors whilst still blocking receptor stimulation by noradrenaline.

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