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Semester 2 - alex > Membranes and Receptors > Flashcards

Membranes and Receptors Flashcards

1
Q

List 5 functions of biological membranes

A
  1. Continuous, highly selective permeability barrier
  2. Control of the enclosed chemical environment
  3. Communication
  4. Recognition - signalling molecules
    - adhesion proteins
    - immune surveillance
  5. Signal generation in response to stimuli.
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2
Q

What is the general dry eight membrane compostion?

A

40% lipid
60% protein
1- 10% carb

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3
Q

What does amphipathic mean?

A

They contain both hydrophilic and a hydrophobic moiety

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4
Q

What is the composition of a phospholipid molecule?

A

Fatty acid chain (all same length- C14-24)
Glycerol
Phosphate
Polar head group (eg choline, amines, amino acids, sugars…)

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5
Q

What causes the kink in the fatty acid tail?

A

Cis double bond

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6
Q

What’re the 2 types of glycolipids?

A

Cerebrosides- sugar monomer head group

Gangliosides- oligosaccharide (sugar multimers) head group

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7
Q

What are the 4 types of motion occurring by the phospholipids in the membrane?

A

Flexing
Rotation
Lateral diffusion
Flip flop

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8
Q

What influence does the cis double bond have in the unsaturated hydrocarbon chains of the membrane?

A

Reduces phospholipid packing

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9
Q

What are the 3 main components of a cholesterol molecule?

A

Polar head group
Rigid planar steroid ring structure
Non-polar hydrocarbon tailor.

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10
Q

What does the rigid steroid ring do in cholesterol?

A

Restrict motion

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11
Q

What is the evidence for protein membranes?

A

Functional:

  • facilitated diffusion
  • ion gradients
  • specificity of cell responses

Biochemical:

  • membrane fractionation and gel electrophoresis
  • freeze fracture
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12
Q

Which fracture face contains the cytosol?

A

P face

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13
Q

What are the 3 modes of motion of proteins in the membrane?

A

Rotation
Conformational change
Lateral diffusion
NO FLIP FLOP

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14
Q

How can mobility of proteins be restricted?

A

Aggregation
Tethering
Interaction with other cells

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15
Q

What causes restraints on protein mobility in the membrane?

A

Lipid mediated effects- separate out into the fluid phase or cholesterol deficient regions
Membrane and peripheral protein associations

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16
Q

What is a peripheral membrane protein?

A

Bound to the surface by electrostatic forces and hydrogen bond interactions. Can be removed by changes in the pH or ionic strength

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17
Q

What is an integral protein?

A

A protein in the membrane that interacts extensively with hydrophobic domains of the lipid bilayer

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18
Q

How are integral proteins removed?

A

By agents that compete for non-polar interactions e.g. Detergents and organic solvents

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19
Q

What is a transmembrane polypeptide.

A

A protein that goes from one side of a membrane through to the other side. Usually contains hydrophobic R groups and exists as a helix

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20
Q

What is membrane protein topology?

A

The location of the N-terminus (inner or outer side of the membrane)

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21
Q

Describe secretory protein synthesis.

9 points

A
  1. Free ribosomes initiate protein synthesis from mRNA molecule.
  2. Hydrophobic N-terminal signal sequence is produced.
  3. Signal sequence is recognised and bound to by the SRP
  4. Protein synthesis stops
  5. GTP-bound SRP directs the ribosome synthesising the protein to SRP receptors on the cytosolic face of the ER.
  6. SRP dissociation
  7. Protein synthesis continues and the newly formed polypeptide is fed into the ER via a pore in the membrane (peptide translocation complex)
  8. Signal sequence is removed by a signal peptidase once the entire protein has been synthesised.
  9. The ribosome dissociates and is recycled.
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22
Q

What additional step is there in membrane protein synthesis compared to secretory protein synthesis?

A

stop transfer signal.
When the membrane protein is being translated into the ER lumen, the ribosome comes across a highly hydrophobic stop transfer signal.

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23
Q

What does a hydropathy plot show?

A

How many transmembrane regions a protein has.

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24
Q

What is membrane asymmetry important?

A

For function. Position of the recognition site is important.

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25
Q

How does the cis formation of the unsaturated fatty acid side chains affect fluidity?

A

introduces a kink in the chain that reduces phospholipid packaging which increases membrane fluidity.

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26
Q

How does cholesterol stabilise the plasma membrane?

A

By hydrogen bonds to he fatty acid chains. This abolishes the endothermic phase transition of phospholipid bilayers.

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27
Q

How does cholesterol increase membrane fluidity?

A

Reduces phospholipid packing. However it also reduces phospholipid chain motion, decreasing membrane fluidity.

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28
Q

Why is the plasma membrane referred to as a fluid mosaic model?

A

fluid- it is not solid due to the hydrophobic integral components such as lipids and membrane proteins that move laterally throughout the membrane.
Mosaic- Made up of many different parts…

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29
Q

What effects lateral diffusion of proteins through the the membrane?

A 
Size
Protein aggregation
Association 
Lipid mediated effects
Proteins tend to separate out into fluid phase or cholesterol poor regions.
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30
Q

What composes the erythrocyte cytoskeleton/

A

Spectrin actin molecules attached to the membrane by adapter proteins Ankyrin and Glycophorin.

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31
Q

How does the cytoskeleton effect mobility of membrane proteins?

A

restricts lateral mobility by attachment to integral membrane proteins

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32
Q

What happens to erythrocytes without the cytoskeleton?

A

More spherical and lysed by shearing forces in capillary beds and cleared by the spleen

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33
Q

What is hereditary spherocytosis?

A

Spectrin levels depleted (by 40-50% in dominant form) resulting in rounding up and increased lysis of cells reducing RBC lifespan. This leads to haemolytic anaemia as the bone marrow cannot compensate.

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34
Q

What is hereditary elliptocytosis?

A

Spectrin molecules are unable to from heterotetramers resulting in fragile elliptoid cells which leads to haemolytic anaemias

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35
Q

Describe passive diffusion.

A

Dependent on permeability and concentration gradient with the rate of passive transport increasing linearly with increasing concentration gradient.

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36
Q

Describe facilitated diffusion.

A

Diffusion across the membrane with the help of a specific protein in the bilayer eg carrier protein or protein channels.

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37
Q

Describe active transport.

A

Transport of ions or molecules against an unfavourable concentration gradient and/or electrical gradient, requiring energy form ATP.

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38
Q

What are co-transporters?

A

Membrane transporters that transport more than one molecule.

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39
Q

What is a uniport?

A

Single transport molecule working in one direction

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40
Q

What is a symport?

A

A unit that transports 2 molecules in the same direction

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41
Q

What is an antiport?

A

A unit that transports 2 molecules in opposite directions.

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42
Q

What binds to the alpha subunit in the Na/K pump?

A

K
Na
ATP
Oubain

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43
Q

What binds to the beta subunit of the Na/K pump?

A

Glycoprotein which directs the pump to the surface.

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44
Q

What does oubain do?

A

Inhibits Na, K and ATP binding

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45
Q

What type of transport does Na/K ATPase involve?

A

Antiport- 2K in, 3Na out

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46
Q

What are the results of transport from the Na/K pump?

A

Forms NA and K gradient necessary for electrical excitability which drives secondary active transport

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47
Q

How does Na and K regulation effect the cell?

A 
Control of pH
Regulation of cell volume
Regulation of Ca2+ conc
Absorption of Na in epithelia
Nutrition uptake
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48
Q

What does PMCA do?

A

Regulates Ca using ATP.
Expels Ca for the cell in exchange for H ions making the cell more alkaline.
High affinity, low capacity

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49
Q

What does SERCA do?

A

Transports Ca into the SR in exchange for H.
High affinity, low capacity
Removes residual Ca

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50
Q

What does NCX exchange?

A

1 Ca out for 3 Na in

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51
Q

How does NCX work?

A

Uses the Na concentration gradient set up by Na/K ATPase antiport
Membrane potential dependent.
Low affinity high capacity

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52
Q

How does NCX change in activity in ischaemia?

A

Sodium pump is inhibited due to ATP depletion

Na accumulates in the cell so NCX reverses

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53
Q

Name the main acid extruders.

A

NHE - Na/H Exchanger

NBC - Sodium Bicarbonate Co-Transporter

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54
Q

How does NHE work?

A

Exchanges Na for intracellular H raising the inrtracellular pH

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55
Q

What activate NHE?

A

growth factors

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56
Q

What inhibits NHE?

A

amiloride

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57
Q

Other than being an acid extruder, what other function does NHE have?

A

Regulates cell volume

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58
Q

What other function does NBC have?

A

Involved in regulating cell volume

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59
Q

What is the bodies main base extruder?

A

AE - Anion Exchanger. Cl/HCO3 exchanger

Removes base from the cell

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60
Q

What is another function of the base extruder?

A

cell volume regulation

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61
Q

How does ion transport regulate cell volume?

A

Water follows the ions, causing cell shrinkage or swelling.

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62
Q

Why is the Na/K pump important in the proximal tubule?

A

Keeps intracellular Na conc low so NHE can pump H ions into the proximal tubule lumen.

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63
Q

What is the importance of H in the proximal tubule?

A

“Picks up” bicarbonate and brings it back into the cell

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64
Q

What is the aim of anti-hypertensive therapy?

A

Reduce the reuptake of Na and other molecules so less water is reabsorbed via osmosis
With less water being absorbed, blood volume and therefore pressure will fall

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65
Q

What does aquaporin do?

A

Allows water to readily cross the membrane of the proximal tubule. It’s inclusion in the membrane is stimulated by anti-diuretic hormone

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66
Q

What are loop diuretics?

A

Block Na reuptake in the thick ascending limb of the prox. convoluted tubule

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67
Q

What works in the prox and distal convoluted tubules to prevent Na uptake?

A

Amiloride

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68
Q

What does aldosterone do in the kidneys?

A

Works to up-regulate sodium transporters in the prox and distal convoluted tubule

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69
Q

What is used to treat abnormally high levels of aldosterone?

A

Spironolactone (Glucocorticoid receptor antagonist)

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70
Q

How does Na transport by the Na/K pump afftect Cl?

A

Allows the symport of 2Cl into the cell with Na and K

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71
Q

What causes cystic fibrosis?

A

Faulty CFTR protein leads to accumulation of C ini the cell, water moves into the cell by osmosis leading to thick, viscous mucous in the lumen.

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72
Q

How does diarrhoea occur?

A

CFTR is overly active and phosphorylated by Protein Kinase A
Cl is excessively transported into the lumen
Water follows, giving the symptoms of diarrhoea

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73
Q

What is a membrane potential?

A

The electrical potenetial difference across a cell membrane.

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74
Q

What is the resting membrane potential?

A

Potential inside the cell relative to teh extracellular solution

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75
Q

How can a membrane potential be measured?

A

Using a micorelectrode which penetrates the cell membrane and is filled with conducting solution (KCL)

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76
Q

What is the range of animal cell membrane potentials at rest?

A

-20 to -90mV

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77
Q

What part of the body has the largest resting potential?

A

Cardiac and skeletal muscle -80 to -90mV

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78
Q

What is the resting potential of nerve cells?

A

-50 to -75mV

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79
Q

What determines what the membrane selectively permeable to ions?

A

Protein channels.

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80
Q

How is the resting potential of the cell set up?

A

The selectivity of ion channels and the type of channels that are open make the whole cell membrane selectively permeable to ions which determine the potential

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81
Q

What ion dominates the membrane ionic permeability at rest?

A

potassium

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82
Q

How does K set up the membrane potential?

A

When chemical and electrical gradients of K are equal and opposite, there is no net movement of K but there will be a negative membrane potential.

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83
Q

What is the equilibrium potential for an ion?

A

the membrane potential at which there is no net movement of the ion across the membrane

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84
Q

What is used to calculate the equilibrium potential?

A

The Nernst equation

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85
Q

Define depolarisation

A

The membrane potential decreases in size (but not necessarily enough to form an action potential - may be v small change) Cell interior becomes less negative

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86
Q

Define hyperpolarisation

A

Membrane potential increases in size - falls below resting. Cell interior becomes more negative

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87
Q

Where do synaptic connections occur?

A

between nerve, muscle, sensory cells and glands

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88
Q

What type of synaptic transmission are there?

A

Fast and Slow

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89
Q

What is fast synaptic transmission?

A

The receptor protein is also an ion channel. Binding of transmitter causes the channel to open

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90
Q

What is slow synaptic transmission?

A

The receptor protein and ion channel are separate. May be linked by a G protein or intracellular messengers

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91
Q

What do excitatory transmitters do?

A

Open ligand-gated channels causing membrane depolarisation

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92
Q

What is an EPSP?

A

Excitatory Post Synaptic Potential
Has a longer time course than an AP
Graded with the amount of transmitter (acetylcholine, glutamate)

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93
Q

What do inhibitory transmitters do?

A

Open ligand-gated channels causing hyperpolarisation - permeable to K or Cl

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94
Q

What is an IPSP?

A

Inhibitory Post Synaptic Potential

Transmitters include Glycine, gama-aminobutyric acid (GABA)

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95
Q

What is an action potential?

A

Change in voltage across the membrane
Depends on ionic gradient and relative permeability of the membrane
Only occurs if a threshold value is reached - All or nothing
Propagated without loss of amplitude

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96
Q

On investigation of the mechanism of action potential generation, what does voltage-clamping do?

A

Controls the membrane potential so that the ionic currents can be measured

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97
Q

What does path clamping do?

A

Enables currents flowing rough individual ion channels to be measured

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98
Q

What is the mechanism of the upstroke of the AP?

A

Positive feedback of the depolarisation of the membrane on opening of the Na channels

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99
Q

How is the cell repolarized?

A

Further depolarisation causes the Na channels to shut and the K channels to open causing repolarisation

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100
Q

What is an ARP?

A

Nearly all Na channels are in the activated state

Absolute Refractory Period

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101
Q

What is the RRP?

A

Na channels are recovering from inactivation, the excitability returns to towards normal as the number of channels in the inactivated state decreases

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102
Q

What is accommodation?

A

The longer the stimulus, the larger the depolarisation necessary to initiate an action potential - the threshold becomes more positive

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103
Q

In a voltage gated Na channel, which subunit (?) is the voltage sensor?

A

4 - has a positive amino acid residue

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104
Q

What does the P or H5 region contribute to?

A

Pore selectivity

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105
Q

How do many local anaesthetics work?

A

By blocking Na channels

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106
Q

In what order do local anaesthetics block axons?

A
  1. Small myelinated
  2. Un-myelinated
  3. Large myelinated
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107
Q

Name 2 diseases that affect conduction of an action potential in the CNS

A

Multiple Sclerosis - All CNS nerves

Devics disease - Optic and Spinal nerve only

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108
Q

Name 2 diseases that affect conduction of an action potential in the PNS

A

Landry-Guillin-Barre syndrome

Charcot-Marie-Tooth disease

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109
Q

What is capacitance?

A

The ability to store charge - a property of the lipid bilayer

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110
Q

What does membrane dependence rely on?

A

The number of ion channels open - lower resistance, more channels open

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111
Q

What does the spread of local current depend on?

A

Capacitance and membrane resistance

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112
Q

What causes the rapid upstroke of the AP?

A

Influx of Na

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113
Q

What increases the rate of the spread of the action potential?

A

High resistance and low capacitance

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114
Q

What happens if the myelin sheath is damaged?

A

Saltatory conduction is inhibited

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115
Q

How does an action potential cause Ca channels to open?

A

The depolarisation of the membrane causes the voltage gated channels to open.

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116
Q

How do Ca channels differ?

A

Affected by different blockers

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117
Q

How is the difference in Ca channels beneficial?

A

Localised effect of blockers - Different channels have different primary locations

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118
Q

How is the high density of Ca channels at nerve endings beneficial?

A

Provides a large enough influx of Ca to trigger Ach release

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119
Q

How does Ca cause the release of Ach?

A

Binds to Synaptotagmin, leading to the formation of the Snare Complex and Ach release

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120
Q

What does binding of Ach with nicotinic receptors on the post-junctional membrane produce?

A

An end-plate potential

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121
Q

What does this depolarisation of the end plate do?

A

Raises the muscle above threshold so an action potential is evoked in the muscle membrane

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122
Q

Name 2 types of blockers that work on nicotinic receptors

A

competitive

depolarising

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123
Q

How do competitive nicotinic blockers work?

A

Bind at the molecular recognition site for Ach

eg. Tubocurarine

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124
Q

How do depolarising nicotinic blockers work?

A

Cause a maintained depolarisation at the post-junctional membrane. Adjacent Na channels will not be activated due to accommodation
eg. Succinylcholine

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125
Q

What is Myasthenia Gravis?

A

Autoimmune disease targeting nicotinic receptors

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126
Q

What are the symptoms of Myasthenia Gravis?

A

Drooping eyelids
Weakness
fatigue

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127
Q

How is Myasthenia Gravis treated?

A

Ach-esterase inhibitors. Increase the amount of time Ach is in the synaptic cleft

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128
Q

Why is it important to regulate intracellular Ca?

A

Many cellular processes are Ca sensitive and it cannot be metabolised.

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129
Q

How is Ca regulated?

A

Largely by moving Ca into and out of the cytoplasm

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130
Q

What are the advantages and disadvantages of the large Ca gradient?

A

Advantages- Changes in intracellular Ca occur rapidly with little movement
Disadvantages- Ca overload leads to loss of regulation and cell death

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131
Q

What does the Ca gradient rely on?

A

Relative impermeability of the membrane
Ability to expel Ca (using Ca ATPase and Na/Ca exchanger
Ca Buffers
Intracellular Ca stores (rapidly and non rapidly releasable)

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132
Q

What is the relative impermeability of the membrane dependent on?

A

open/closed state of the ion channels

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133
Q

How do Ca buffers effect Ca gradient?

A

Limit diffusion through ATP and Ca binding proteins

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134
Q

Name 4 proteins which may act as Ca buffers

A

Parvalbumin
Calreticulin
Calbindin
Calsequestin

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135
Q

What does diffusion of Ca depend on with regards to buffers?

A

THe conc of binding molecule and it’s level of saturation

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136
Q

What is the basal concentration of Ca in most cells?

A

100nm

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137
Q

What level can the Ca concentration rise to when it is being used to regulate cell activity?

A

1 micrometer

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138
Q

How is the concentration of Ca altered?

A

Influx across the plasma membrane
Release from “rapidly releasable” stores
Release from “non-rapidly releasable” stores

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139
Q

How is the permeability of the membrane to Ca altered?

A

Voltage-Gated Calcium Channels (VGCC)

Receptor Operated Calcium Channels (Ionotropic receptors - Ligand/agonist binds to the channel)

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140
Q

Where are calcium stores in the cell?

A

Sarco/Endoplasmic reticulum, set up by SERCA protein. Moved in using ATP energy and binds to proteins

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141
Q

What might cause Ca to be released from the sarcoendoplasmic reticulum?

A

ligand binding to G-Protein coupled receptor on the cell membrane, activating its alpha subunit. This then binds to the membrane phosphlipid PIP2 releasing IP3 which in turn binds to its receptor on the sarcoendoplasmic reticulum , triggering the release of Ca down its conc grad.
Ca induced release - Ca binds to the Ryanodine receptor on the S/ER triggering Ca release

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142
Q

Where is CICR physiologically important?

A

Cardiac myocyte

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143
Q

When/why is Ca taken up into the mitochondria?

A

When the Ca conc is high as a protective mechanism. They aid in buffering, regulating signalling and stimulation of ATP production

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144
Q

How do mitochondria take up Ca?

A

Via a uniport driven using respiration

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145
Q

What is required to return Ca to it’s basal level?

A

Terminationi of signal
Ca removal
Ca store refilling

146
Q

What refills the Ca stores?

A

Recycled cyytosolic Ca

Ca in the mitochondria is used to replenish SR stores

147
Q

How is mitochondrial Ca transferred to SR stores?

A

Via store-operated Ca channel (SOC)

148
Q

Define receptor

A

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

149
Q

How are receptors classified?

A

By their specificity to a physiological signalling molecule. They are often divided further on the basis of their affinity to a series of antagonists

150
Q

What are some roles of receptors?

A

Signalling
Neurotransmission
Cellular delivery

151
Q

What is the difference between a receptor and acceptor?

A

Receptors are silent at rest and require a ligand to be activated. Acceptors operate in the absence of ligands

152
Q

Define a ligand

A

A molecule that binds specifically to a receptor site

153
Q

What is an agonist?

A

A ligand that activates a receptor on binding

154
Q

What is an antagonist?

A

A ligand that binds to a receptor without causing activation and blocks the receptor

155
Q

How do hydrophobic molecules travel in the blood and cross membrane barriers?

A

They may require carrier proteins which are hydrophilic to travel in the blood but can diffuse straight across the membrane lipid bilayer (if small enough)

156
Q

Where are receptor sites for small, hydrophobic molecules located?

A

Inside the cell

157
Q

Where are receptor sited for hydrophilic molecules?

A

On the cell surface

158
Q

How do hydrophilic molecules bring about changes inside the cell?

A

Signal transduction. Extracellular receptor at the cell surface transmits the signal into the cell

159
Q

How do membrane bound receptors cause signal transduction?

A

Integral ion channels
Integral enzyme activity
Coupling to effectors through transducing proteins

160
Q

How does agonist binding to a ligand-gated ion channel cause it to open?

A

Brings about conformational change

161
Q

What are classical ligand gated ion channels?

A

Share the similar pentameric subunit structures with four transmembrane domains

162
Q

What happens to Tyrosine Kinase linked receptors upon ligand binding?

A

Autophosphorylate and are recognised either by transducing proteins or directly by enzymes containing phosphtyrosine recognition sites

163
Q

How is the effector enzyme, Tyrosine Kinase activated?

A

On association with the receptor, allosterically activated by tyrosine phosphorylation by the receptor kinase. This transduces the message into an intracellular chemical event

164
Q

What are G protein coupled receptors?

A

7 transmembrane domain receptors couple to effector molecules via a transducing molecule, a GTP binding regulatory protein

165
Q

What are the effectors of G protein coupled receptors?

A

Enzymes or ion channels

166
Q

What is integrated signalling?

A

often G protein coupled receptors will act simultaneously to inhibit and stimulate the effector. The 2 inputs combine to produce a measured effect

167
Q

What are intracellular receptors bound to in their resting state?

A

heat shock or chaperone proteins

168
Q

How do intracellular receptors work?

A

On activation, dissociate from the stabilising protein and translocate to the nucleus where it binds to control regions in DNA, regulating gene expression

169
Q

Do intracellular or extracellular receptors work faster? Why?

A

Exracellular. The action of Intracellular receptors is dependent on transcription and translation

170
Q

Why is amplification often necessary in extracellular signalling?

A

Concentration of extracellular signalling molecules is very low

171
Q

What is amplification?

A

The binding of a chemical signal molecule to a single receptor can cause the modification of many substrate molecules

172
Q

What does noradrenaline bind to to cause an increase in heart rate?

A

Beta-1- adrenoreceptors

173
Q

WHat binds to M2 muscarinic receptors to cause slowing of the heart rate?

A

Acetylcholine

174
Q

Where does phagocytosis occur?

A

Specialised cells - macrophages and neutrophils

175
Q

Describe phagocytosis

A
  1. In response to binding of a particle to receptors in the plasma membrane, the cell extends pseudopods that permit furthur receptor interactions
  2. Membrnae invagination/particle internalisation via a membrane zippering mechanism
  3. Internalised phagosomes fuse with lysosomes to form phagolysosomes in which the particulate material is degraded
176
Q

What does phagocytosis do?

A

Clears damaged cellular material and invading microorganisms

177
Q

What is pinocytosis?

A

The invagination of the plasma membrane to form a lipid vesicle

178
Q

What does pinocytosis do?

A

uptake of impermeable extracellular solutes

179
Q

What are the 2 forms of pinocytosis?

A

Fluid phase

Receptor mediated endocytosis (RME)

180
Q

What is receptor mediated endocytosis?

A

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

181
Q

Where are LDL’s made?

A

Liver

182
Q

What are LDLs made 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

183
Q

What do LDL receptors recognise?

A

Apoprotein B

184
Q

Where are LDL receptors?

A

Cell surfaces, localised in clusters over Clathrin Coated Pits that cover approx 2% of the cells surface (spontaneous formation of pits and clathrin cages)

185
Q

What happens when LDL binds to cell receptors?

A

Pits invaginate and form coated vesicles. Vesicles are uncoated in a process that requires ATP and fuse with smooth vesicles, endosomes

186
Q

What is the pH of the endosome and how is it maintained?

A

5.5-6, lower than the cytoplasm, maintained by ATP dependent proton pump

187
Q

Why does the endosome have a lower pH?

A

LDL receptor has a lower affinity for the LDL particle so dissociate

188
Q

What is the endosome that dissociates the ligands and receptor known as?

A

Compartment for the Uncoupling of Receptor and Ligand (CURL)

189
Q

What happens to the LDL receptor once dissociated from the particle?

A

sequestered to a domain within the endosome membrane which buds off as a vesicle and recycles the LDL-receptor to the plasma membrane

190
Q

What happens to the LDL in the endosomes?

A

Endosomes fuse with lysosomes and the cholesterol is hydrolysed from the esters and released into the cell

191
Q

What are the 3 mutations affecting the LDL receptor?

A

Non-functioning receptor - mutation to the binding site
No interaction of the receptor and clathrin coat so LDL receptors distributed over the entire cell surface
Receptor deficiency - expression of receptors prevented

192
Q

How is transferrin formed in the circulation?

A

Binding of 2 Fe3+ ion to apoptransferrin

193
Q

What happens when transferrin reaches the acidic endosome?

A

Fe ions are released but apoptransferrin remains associated to the transferrin receptor

194
Q

What happens to the apoptransferrin after Fe is dissociated?

A

Sorted in the curl for recycling back to the membrane where apoptransferrin dissociates from the receptor again.

195
Q

When do insulin receptors congregate over clathrin coated pits?

A

When insulin is bound to it - induces a conformational change in the receptor which allows i to be recognised by the pit

196
Q

What happens to insulin in the endosome?

A

It remains bound to the receptor and is targeted to the lysosomes for degradation

197
Q

How is a cell desensitised to a presence of high circulating insulin concentrations?

A

Lack of receptors associated with the cell membrane - only associates when insulin is bound to the receptor

198
Q

What is Transcytosis?

A

Ligands remain bound to their receptors and are transported across the cell

199
Q

How is immunoglobulin A from the circulation transported to bile in the liver?

A

Transcytosis. During transport the receptor is cleaved, resulting in the release of immunoglobulin with a bound secretoroy component derived from the receptor

200
Q

How do membrane enveloped viruses and toxins enter cell?

A

Exploit endocytic pathways after adventitious binding to receptors in the plasma membrane

201
Q

What happens to the membrane enveloped virus once in the endosome?

A

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

202
Q

What are G-proteins?

A

guanine nucleotide binding proteins

203
Q

What is a G-protein coupled receptor?

A

A family of receptors that act by altering the activity of effectors via the activation of a G-protein

204
Q

How are G-proteins hetertrimeric?

A

They have 3 distinct subunits, alpha, beta and gama. B and g are bound tightly together and function as a single unit

205
Q

Where is the guanine nucleotide binding sit on the G-protein?

A

Alpha subunit

206
Q

What does the guanine nucleotide binding site do?

A

Binds to the GTP and slowly hydrolyses it to GDP (GTPase activity)

207
Q

Where is the G-p under basal conditions?

A

the inner face of the plasma membrane in it’s heterotrimeric form (mostly) and GDP bound to the alpha subunit

208
Q

When is the GDP released from the alpha subunit?

A

When an agonist binds to the GPCR and protein protein interactions occur between the heterotrimeric G-p and the receptor. GTP binds in it’s place

209
Q

What happens to the G-p when GTP binds?

A

Affinity of receptor for Alpha GTP and the BG subunit decreases. They are released and are each able to interact with effectors

210
Q

What terminates the effector interaction of G-p subunits?

A

intrinsic GTP activity of the Alpha subunit hydrolysing GTP->GDP.
Affinity of A sub and BG sub increases and the ABG heterotrimer is reformed.

211
Q

Describe the mechanism of action of a G-protein.

A
  • Agonist binds to receptor
  • Protein-protein interactions releases GDP, binds GTP
  • Alpha-GTP and BG released and interact with effectors
  • GTP hydrolysed to GTP
  • Alpha-GDP and BG reform heterotrimer
212
Q

What are 4 G-proteins?

A

Gs
Gi
Gq
Gt

213
Q

What does Gs do?

A

Stimulates adenylyl cyclase

214
Q

What signals Gs?

A

Adrenaline/noradrenaline

215
Q

What receptor does Gs act on?

A

B-adrenoreceptor

216
Q

What physiological response does Gs produce?

A

Glycogenolysis

Lipolysis

217
Q

What does Gi do?

A

Inhibits the action of adenylyl cyclase

Stimulates K channels

218
Q

What signals Gi?

A

Acetylcholine

219
Q

What receptor does Gi act on?

A

M2-Muscarinic

220
Q

What physiological response does Gi evoke?

A

slowing of cardiac pacemaker

221
Q

WHat does Gq do?

A

Stimulate phosphlipase C

222
Q

What signals Gq?

A

Acetylcholine

223
Q

What type of receptors do Gq act on?

A

M3-Muscarinic

224
Q

What physiological response does Gq evoke?

A

Smooth muscle contraction

225
Q

What does Gt do?

A

Stimulates cyclic GMP phosphodiesterase

226
Q

What signals Gt?

A

Light

227
Q

What receptor does Gt act on?

A

Rhodopsin

228
Q

What physiological response does Gt evoke?

A

Visual excitation

229
Q

What receptors does Gs utilise?

A

adrenergic B1 and B2

230
Q

What receptors does Gi utilise?

A

adrenergic A2 and cholinergic M2

231
Q

What receptors does Gq utilise?

A

adrenergic A1 and cholinergic M1 and M3

232
Q

How many G-protein combinations can the human genome encode?

A

1,000 possible combinations
20 alpha
5 beta
12+ gama

233
Q

How many receptor types are there for G-proteins?

A

at least 800

234
Q

How many enzyme/ion channel effectors can each G-p receptor activate?

A

10+

235
Q

What does cholera toxin (CTx) do?

A

Inactivates G-alpha GTPase. G-alpha is permanently activated

236
Q

What does pertussus toxin (PTx) do?

A

Interferes with the GDP->GTP exchange on G-alpha leading to its irreversible inactivation

237
Q

Name 3 diseases caused by mutations in GPCRs.

A

Retinitis pigmentosa
Nephrogenic Diabetes Insipidus
Familial Male Precocious Puberty

238
Q

What causes Retinitis pigmentosa?

A

Loss of function mutation to rhodopsin

239
Q

What causes Nephrogenic Diabetes Insipidus?

A

Loss of function mutation to V2 vasopressin receptor

240
Q

What causes Familial Male Precosious Puberty?

A

Gain of function he Luiteinising Hormone receptor

241
Q

How does cyclic AMP exert the majority of it’s actions?

A

Through cyclic AMP-dependent Protein kinase (PKA)

242
Q

What activity does activation of cyclic AMP receptors cause in the body?

A

Glycogenolysis and gluconeogenesis
Lipolysis
Relaxation of many smooth muscles
Positive inotrophic and chronotrophic effectrs on the heart

243
Q

What does phospholipase C do?

A

Hydrolyses membrane phospholipids to to IP3

244
Q

What does IP3 do?

A

interacts with receptors on ER membrane to activate the release of Ca from the lumen and enter the cytoplasm

245
Q

What does cyclic GMP phosphodiesterase do?

A

found in the photoreceptive cells in the retina

regulates the breakdown of the secondary messenger cyclic GMP phosphodiester

246
Q

How does dissociation of a G-p and receptor occur?

A

Once they have productively interacted, the binding of the agonist is weakened - dissociation occurs

247
Q

How is further interaction with other G-p prevented when the receptor is activated? (receptor desensitisation)

A

When activated, the receptor is susceptible to a variety of protein kinases that phosphorylate the receptor and prevent it activating further G-ps

248
Q

How is the active lifetime of GTP limited?

A

Cellular factors stimulate the intrinsic GTPase activity of the G-alpha subunit

249
Q

What opposes the effect of second messengers/protein kinases downstream?

A

Enzymatic cascades activated

250
Q

What chemical in the body affects the rate at which the SAN fires an action potential?

A

Ach release in the parasympathetic nerves acting on M2 muscarinic cholinoreceptors

251
Q

How does Ach affect heart rate?

A

acts on M2 muscarinic cholinoreceptors to increase the open probability of K channels via Gi -> hyperpolarisation, slowing the intrinsic firing rate.

252
Q

What type of chronotropic effect does Ach have on the heart?

A

Negative chronotropic effect

253
Q

How is inotropy regulated in the heart?

A

Sympathetic innervation of the ventricles and/or adrenaline influence the force of contraction

254
Q

How does the activation of Beta-Adrenoreceptors cause positive inotropic effects?

A

Increased probability of open VOCCs, directly and indirectly by the activation of Gs. Influx of Ca causes positive inotropic effects.

255
Q

How is arteriolar vasoconstriction initiated in the heart?

A

Sympathetic release of noradrenaline activated Alpha1-adrenoreceptors to stimulate phosphlipase C and IP3 production via Gq. IP3 releases ER Ca and initiates a contractile response

256
Q

What stimulates Mu-opiod receptors?

A

endogenous opiods or by analgesics eg morphine to couple G-alpha1 proteins

257
Q

How do G proteins reduce neurotransmitter release?

A

G- beta-gama subunits, liberated from teh heterotrimer interact with VOCCs to reduce Ca entry, reducing neurotransmitter release

258
Q

How do drugs exert their effects?

A

Bind to a target (Mostly proteins)
Mostly reversibly
Binding by association and dissociation rates

259
Q

Name the 2 most common targets for drugs

A

Enzymes (47%)

GPCRs (30%)

260
Q

What are 3 other drug targets?

A 
Ion channels
Transporters
Nuclear hormone receptors
Receptors
Integrins 
Misc
261
Q

When do drugs have the same concentration of molecules?

A

When they have the same molar concentrations. NOT WHEN THEY ARE OF EQUAL WEIGHT

262
Q

How many particles does 1 mole contain?

A

6 x10^23

263
Q

What does “1 molar solution” mean?

A

1 mole in 1 litre

264
Q

Define Affinity

A

Likelihood of a ligand binding to its target

265
Q

Define efficacy

A

Likelihood of activation

266
Q

What drugs have both affinity and efficacy?

A

agonists

267
Q

What drugs have affinity but no efficacy?

A

antagonists

268
Q

What is a radioligand and why might one be used?

A

A radioactive ligand often used to obtain information on binding

269
Q

What does Bmax show?

A

Maximum binding capacity. This gives information about the number of receptors

270
Q

What is Kd?

A

dissociation constant. A measure of affinity. The concentration needed for 50% occupancy
(lower Kd, higher affinity)

271
Q

What type of graph is used to measure response in cells/tissue?

A

concentration response curves

272
Q

When is a dose response curve used?

A

to measure response in a whole animal

273
Q

What is Emax?

A

Maximum response

274
Q

What is EC50?

A

Effective concentration giving 50% of the maximal response. A measure of potency.

275
Q

What is potency?

A

A combination of affinity and efficacy. The number of receptors also governs potency

276
Q

Do agonists with the same Emax have the same efficacy?

A

No, may have different affinity

277
Q

How can less than 100% receptor occupancy give a 100% response?

A

Spare receptors are present (receptor reserve) - more receptors than required to produce a maximal response.

278
Q

What influences the relationship between receptor occupancy and response?

A

transduction system/amplification produced by second messengers and the properties of the tissue

279
Q

What do spare receptors do?

A

increase sensitivity allowing for response at low conc of agonist. No. of receptors therefore has an effect on potency

280
Q

What drug is used as pain relief and recreationally?

A

Opioid (heroin)

281
Q

What negative side effects can opioid have?

A

Respiratory depression leading to death

282
Q

How do opioids work in the body?

A

Primarily through Mu-Opioid receptors (GPCR)

283
Q

What is a partial agonist of the same receptors of which morphine is a full agonist?

A

Buprenorphine. Higher affinity, lower efficacy

284
Q

Why is buprenorphine sometimes a better option than morphine?

A

Less respiratory depression. Used if adequate pain control as it is only a partial agonist

285
Q

What are the 3 different types of antagonists?

A

Reversible competitive
Irreversible competitive
Non-competitive

286
Q

What does reversible competitive antagonism rely on?

A

Dynamic equilibrium between ligand and receptors

287
Q

What is the most commonly used type of antagonist?

A

Reversible competitive

288
Q

How can the effect of competitive antagonists be overcome?

A

Increased amount of agonist - graph shifts left

289
Q

Give an example of a reversible antagonist

A

Naloxone. High affinity for Mu-opioid receptors. Reverses Mu-opioid receptor respiratory depresssion. High affinity- competes effectively

290
Q

What is an irreversible competitive antagonist?

A

Agonists dissociates slowly or not at all

291
Q

How does irreversible antagonist affect a graph of agonist against response?

A

Shifts the graph to the right as the antagonist is increased before decreasing the max response as the antagonist binds irreversibly and not enough receptors free to illicit a max response

292
Q

Give an example of an irreversible antagonist.

A

Phenoxybenzamine. Non selective alpha1-adrenoreceptor used in hypertension episodes in phenochromocytoma

293
Q

How does a non-competitive antagonist work?

A

allosterically binds to a receptor

294
Q

How does irreversible antagonist affect a graph of agonist against response?

A

Shifts the graph to the right as the antagonist is increased before decreasing the max response as the antagonist binds irreversibly and not enough receptors free to illicit a max response

295
Q

Give an example of an irreversible antagonist.

A

Phenoxybenzamine. Non selective alpha1-adrenoreceptor used in hypertension episodes in phenochromocytoma

296
Q

How does a non-competitive antagonist work?

A

allosterically binds to a receptor

297
Q

Define Pharmacokinetics

A

What the body does to the drug

298
Q

What are the possible formulations of a drug?

A

Solid

Liquid

299
Q

What are the sites of administration of a drug?

A

Local (eye, skin, inhalation etc)
Systemic - Enteral (sublingual, oral, rectal), Parental (subcutaneous, intramuscular, IV injection, inhalation, transdermal)

300
Q

Define oral bioavailability

A

The proportion of a dose given orally (or by any other route other than IV) that reaches the systemic circulation in an unchanged form.

301
Q

How can oral bioavailability be expressed?

A

Amount - Measured by area under the curve of blood drug

Rate - Measured by peak height and rate of rise of drug level in blood

302
Q

What is the therapeutic Ratio?

A

Max. Tolerated Dose/Min. Effective Dose

Lethal Dose to 50%) LD50/ED50 (Effective Dose in 50% of people

303
Q

What is the first pass effect?

A

Substances absorbed from the lumen enter the venous blood, which drains into the hepatic portal vein and is transported directly to the liver which is the main site of drug metabolism as it contains all of the necessary enzyme systems -> drugs absorbed from the lumen extensively metabolised in this first pass through the liver

304
Q

What types of drug administration avoid the first pass effect?

A

parenteral
sublingual
rectal

90% of oral dose is usually metabolised in first pass

305
Q

What is drug distribution?

A

The theoretical volume into which a drug has distributed assuming this is occurring instantly

306
Q

How do you calculate drug distribution?

A

Amount given/plasma conc at time 0

307
Q

In the plasma, what drugs exert their effect?

A

Free level of drugs not the total

308
Q

When is protein interaction of drugs important?

A

When it is highly bound to albumin
Has a small volume of distribution
Has a low therapeutic index

309
Q

What are Class I Drugs?

A

Drugs used at a dose that is much lower than the number of albumin binding sites

310
Q

What are Class II Drugs?

A

Drugs used at a dose that is greater than the number of available binding sites

311
Q

What happens when Class I and II are administered together?

A

Class I is displaced by Class II, raising the levels of the object drug and therefore, higher risk of toxicity

312
Q

What are first order kinetics?

A

Rate of elimination is proportional to drug level. Constant fraction of drug eliminated in unit time. Half life can be defined as the rate of decline of plasma drug level is proportional to drug level

313
Q

What are zero order kinetics?

A

Rate of elimination is constant.
Enzyme is saturated
Steady state is reached within 5 half lives. If an immediate effect is necessary, a loading dose is therefore needed

314
Q

On what graph is a first order kinetic linear?

A

Log Y axis plotted against time

315
Q

On what graph is a zero order kinetic linear?

A

Linear Y axis scale plotted against time

316
Q

When do drugs tend to have zero order?

A

At high doses - metabolism is constant and independent of dose

317
Q

When do drugs tend to have first order?

A

Low doses - metabolism is proportional to dose

318
Q

Compare the response of 1st and zero order kinetics

A

1st - predictable therapeutic response from dose increases

zero - therapeutic response can suddenly escalate quickly as elimination mechanisms saturate

319
Q

What does Phase I do to a drug?

A

Exposes/adds a reactive group if the parent molecule is unreactive, generating an intermediate

320
Q

What reactions commonly occur in phase I of drug metabolism?

A

Oxidation
Reduction
Hydrolysis

321
Q

What complex enzyme system is required for phase I?

A 
cytochrome P450 (CYP) and a high energy cofactor, (NADPH) 
Enzymes are inducible and inhibitable
322
Q

What happens in phase II of drug metabolism?

A

reactive intermediate is conjugated with a polar molecule to form a water soluble complex - conjugation

323
Q

What are common conjugates for phase II drug metabolism?

A

Glucoronic acid is the most common conjugate as it is an available by-product of cell metabolism.
Sulphate ions and glutathione also used.

324
Q

What specific enzymes and cofactors does phase II drug metabolism require?

A

uridine diphosphate glucuronic acid (UDPGA)

325
Q

What effects drug excretion by the kidneys?

A

Only free, unbound drug is filtered through the glomerular tuft
Drugs can be actively secreted by the tubule
Urine pH can determine how much of the drug is excreted

326
Q

How does pH effect the excretion of drugs in the kidney?

A

Weak acidic drugs, making the urine more alkaline will make the drug ionised, so there will be less tubular absorption because the charged drugs stay in the tubule lumen. (Opposite for weak alkali)

327
Q

What does the ANS do?

A

Controls all involuntary (vegetative) functions

328
Q

What type of nerves does the ANS use?

A

Entirely efferent but regulated by afferent inputs

329
Q

What does the sympathetic nervous system do?

A

Responds to stressful situations - fight or flight

330
Q

What does the parasympathetic nervous system do?

A

Regulates basal activities

331
Q

Are ANS nerves myelinated or unmyelinated?

A

Myelinated pre, unmyelinated post

332
Q

Where do parasympathetic nerves originate?

A

Lateral horn of the medulla and sacral regions of the spinal cord

333
Q

Where are the ganglia of the parasympathetic nervous system located?

A

in the tissues innervated by the postsynaptic fibres

334
Q

WHere do sympathetic nerves originate from?

A

The lateral horn of the lumbar and thoracic cord

335
Q

Where are the ganglia of the sympathetic nervous system located?

A

paravertebral chain close to the spinal cord

336
Q

What is the neurotransmitter used in preganglionic neurones in the ANS?

A

Ach
Cholinergic neurons
Activate post-ganglionic nicotinic Ach receptors - ligand gated ion channels

337
Q

What neurotransmitter is released by post-ganglionic parasympathetic neurons and what type of receptors does it act on?

A

Ach
Acts on muscarinic Ach receptors in the target tissue
GPCRs

338
Q

What neurotransmitter is commonly released fro post-ganglionic sympathetic neurones?

A

Noradrenaline - noradrenergic
acts on alpha-adrenoreceptors and beta receptors (1 and 2 and beta 3)
GPCRs

339
Q

What structures are innervated by cholinergic sympathetic post-ganglionic neurones?

A

Sweat glands

Hair follicles

340
Q

What are NANC transmitters?

A

Non-Adrenergic, Non-Cholinergic transmitters
May be co-released with either NA or Ach e.g. ATP, Nitric Oxide, Serotonin, Neuropeptides

Some ANS transmitters behave like this

341
Q

What are chromaffin cells and how are they innervated?

A

Present in adrenal gland - neurons differentiate to form chromaffin cells. They can be considered as postganglionic sympathetic neurons that do not project to a target tissue. On sympathetic stimulation, release adrenaline in to the blood stream.
Innervated by preganglionic sympathetic neurons

342
Q

What are some ANS disorders?

A 
Catecholamine disorders
Central autonomic disorders
Orthostatic intolerence syndrome
Paroxysmal autonomic syncopes
Peripheral autonomic disorders
343
Q

What steps neurotransmission are commonly exploited by drug actions?

A 
Degradation of transmitter
Interaction with post-synaptic receptors 
Inactivation of transmitter
Re-uptake of transmitter
Interaction with pre-synaptic receptors
344
Q

What is acetylchoine made of?

A

Acetyl CoA and choline, catalysed by choline acetyltransferase

345
Q

What is acetylcholine degraded to?

A

Acetate and choline by acetylcholine esterase

346
Q

What are ganglion blockers?

A

Drugs that have actions selectively at autonomic ganglia - nicotinic acetylcholine receptors at autonomic ganglia and neuromuscular junction differ in structure

347
Q

How many types of muscarinic acetylcholine receptors are there?

A

5 but there are relatively few subtype-selective mAchR agonist or antagonists.

348
Q

What do AChE inhibitors do?

A

Enhance the actions of endogenously released ACh

349
Q

Why do cholinergic drugs often associate with unwanted side effects?

A

Relative lack of selectivity

350
Q

What is pilocarpine and when is it used?

A

Muscarinic ACh receptor agonist used to treat glaucoma

351
Q

What is bethanechol?

A

Muscarinic ACh receptor agonist used to sttimulate bladder emptying

352
Q

Name 3 drugs used to treat an overactive bladder

A

tolterodine
darifenacin
oxybutynin

Muscarinic ACh receptor agonists
Severe dry mouth affects compliance

353
Q

WHat is tiotropium?

A

M ACh receptor antagonist used to treat chronic obstructive pulmonary disease

354
Q

What is ipratropium?

A

M ACh antagonist used to treat some forms of asthma

355
Q

What are varicosities?

A

Sites on the highly branched axonal network of hte post ganglionic sympathetic neurons which are specialised for Ca dependent noradrenaline release

356
Q

How is noradrenaline removed from the synaptic cleft?

A

By noradrenaline transporter proteins (high affinity) or if not, re-captured by a lower affinity non-neuronal mechanism- actions terminated by re-uptake

357
Q

What metabolises NA?

A

monoamine oxidase or catechol-O-methyltransferase if not taken up into vesicles in the pre-synaptic terminal

358
Q

How is neurotransmitter release modulated?

A

Presynaptic G protein coupled receptors can regulate neurotransmitter release by inhibiting Ca dependent exocytosis - BG subunits inhibit specific types of voltage operated Ca channels reducingCa influx and neurotransmitter release

359
Q

What are indirectly-acting sympathomimetic agents?

A

Taken up into noradrenergic synaptic vesicles where they cause noradrenaline to leak from the vesicle. Displaced noradrenaline leaks into the synaptic cleft by a mechanism other than Ca mediated exocytosis

360
Q

What are uptake 1 inhibitors?

A

Selective noradrenaline re-uptake inhibitors - mostly work on the CVS. Peripheral actins tend to be unwanted side effects

Semester 2 - alex (4 decks)

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