Pharmacology Flashcards
What is the ENS?
All the neurones (cell bodies) embedded in the wall of the GI tract
What is an efferent nerve?
Motor nerve
What is an afferent nerve?
Sensory nerve
Which ANS reflexes can we exert some conciuos influence on with training?
Micturition, Deffication and accommodation in the eye
What is a ganglion?
A group of nerve cell bodies outside the CNS
What is a nucleus?
A group of nerve cell bodies inside the CNS
Where is the sympathetic outflow?
Thoracolumbar outflow T1-L2
In sympathetic neurones what is the neurotransmitter released by the preganglionic neurone?
ACh
In sympathetic neurones what is the neurotransmitter released by the postganglionic neurone?
Normally NA
In parasympathetic neurones what is the neurotransmitter released by the preganglionic neurone?
ACh
In parasympathetic neurones what is the neurotransmitter released by the postganglionic neurone?
ACh
Where is the parasympathetic outflow?
Cranialsacral outflow CN 3, 7, 9 and 10 and S2-S4
What receptors are used for the neurotransmitter ACh in the autonomic ganglia?
Nicotinic cholinoreceptors
What receptors are used for the neurotrasmitter ACh at effector cells/organs?
Muscarinic Cholinergic receptors
What receptors are used for the neurotransmitter NA at effector cells/organs?
Adrenoceptors
Where do sympathetic neurones synapse?
Within the sympathetic chain- paravertebral ganglia
Outside of the sympathetic chain- prevertebral ganglia
Sympathetic preganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
a) short
b) myelinated (white)
c) Motor B fibres
Sympathetic post ganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
a) long
b) unmyelinated (grey)
c) motor C fibres
Paraympathetic preganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
a) long
b) myelinated (white)
c) motor B fibres
Paraympathetic post ganglionic neurones are typically:
a) long/short?
b) myelinated/ unmyelinated
c) motor B/motor C fibres
a) short
b) unmyelinated (grey)
c) motor C fibres
What is the sympathetic innervation to the adrenal medulla (chromaffin cells)?
Preganglionic neurones via splanchnic nerves and the the neurotransmitter is ACh
What are 4 important abdominal pre vertebral ganglia in the sympathetic system?
Coeliac (liver, stomch and pancreas)
Aortocorticorenal (adrenal gland and kidneys)
Superior mesenertic (accending colon, illeum)
Inferior mesenteric (descending colon, rectum, anus and genitalia)
Where are preganglionic fibre cell bodies located in the spinal cord?
Lateral horn
How do sympathetics get from the lateral horn to the organs?
Anterior rootlets, anterior roots, spinal nerve, (anterior) rami, synapse at
a) paravertebral ganglia and post synaptic nerves join peripheral nerves (grey rami communicants) to organs
b) pre vertebral ganglia ad post synaptic neurones travel in splanchnic nerves to organs
What are chromaffin cells?
Modified post ganglionic neurones which secrete adrenaline (80%) and noradrenaline (20%) into the capillary circulation as hormones
What type of neurotransmitter is released by post ganglionic sympathetic neurones which innervate the thermoregulatory (eccrine) sweat glands and a few blood vessels?
ACh and they act on muscarinic cholinergic receptors
What are the neurotransmitters, other than NA is often used by the sympathetic nerves?
ATP and neuropeptide Y (NPY)
Where are parasympathetic ganglia usually located?
In the walls of target organs
Where are parasympathetic fibre cell bodies located?
Brainstem (mid brain, pons, medulla oblongata)
Sacral segment of the spinal cord
Where is the origin, ganglion and effector target for CN III (oculomotor)?
Origin = Midbrain Ganglion = Ciliary Target = Eye pupillary constrictor
Where is the origin, ganglion and effector target for CN VII (facial)?
Origin = Pons Ganglion = Pterygopalatine and Submandibular Target = Lacriminal glands (nasal cavity) and submandibular and sublingal glands.
Where is the origin, ganglion and effector target for CN IX (glossopharngeal)?
Origin = Medulla oblongata Ganglion = Otic Target = Parotid Gland
Where is the origin, ganglion and effector target for CN X (vagus)?
Origin = Medulla Oblongata Ganglion = Many Target = Lots
What are the neurotransmitters, other than ACh is often used by the parasympathetic nerves?
NO nitric oxide
vasoactive intestinal peptide VIP
Release of what ion triggers action potentials to travel along and between neurones?
Ca++
What is a NANC?
Non adrenergic, non cholinergic transmission.
Where the post ganglionic neurone does not release NA or ACh
Which NANC neurone transmitters can be released and for what seed of response?
Parasympathetic = VIP (slow response) and NO (intermediate response) Sympathetic = ATP (fast respose) NPY (slow response)
What are nicotinic ACh receptors of the ganglia?
Ligand gated ion channels activated by nicotine
NB: structurally and pharmacologically different from nicotinic receptors at neuromuscular junctions or in CNS
What are muscarinic ACh receptors of effector cells?
G protein coupled receptors activated by muscarine
5 subtypes M1-M5 which are differentially expressed across organs
What are adrenoreceptors?
G protein coupled receptors.
Alpha 1 + 2, Beta 1, 2 and 3.
Alpha 1 and 2 are divided into 1(A, B and D) and 2(A, B and C)
What are the activators of alpha 1 adrenoreceptors?
NA > A > Isoprenalinie
What are the activators of alpha 2 adrenoreceptors?
Isoprenaline > A > NA
Micturation reflex: What happens during bladder filling?
Sympathetic activity predominates
Detrusor is relaxed by NA acting on beta 2 and 3 adrenoceptors
Internal urethral sphincre is constricted by NA acting on alpha 1 receptors
Micturation reflex: What happens during bladder vioding?
Parasympathetic activity predominates
Detrusor is contracted by ACh acting on M3 receptors
Internal urinary sphincter is relaxed by NO release that stimulates the production of cGMP (relaxant)
Micturation reflex: How do we voluntarily control the external urethral sphincter?
Somatic efferents (motor) and the release of ACh on cholinergic receptors
What is the bladder detrusor?
Smooth muscle wall
What is the Bladder trigone?
Smooth muscle triangular region formed by the 2 uteric orifices (from kidney) and the internal urethral orifice (sphincre)
Sympathetic//which receptors where?
Heart
Beta 1 adrenoceptors
Increase HR and force of contraction
Sympathetic//which receptors where?
Lungs
Beta 2 adrenoceptors
Relax bronchi, decrease mucus production
Sympathetic//which receptors where?
GI tract?
Alpha 1, 2 and beta 2 receptors
Decrease GI motility and constrict sphincters
Sympathetic//which receptors where?
Adrenal gland
Nicotinic ACh receptor
Release of adrenaline
Sympathetic//which receptors where?
Bladder
Beta 2 and 3 adrenoceptors
Relax detrusor
Alpha 1 adrenoceptors
Constricts the internal urethral sphincre
Sympathetic//which receptors where?
Penis
Alpha 1 adrenoceptor
Ejaculation
Sympathetic//which receptors where?
Vasculature?
alpha 1 adrenoceptors (most locations)
Constricts vasculature
Beta 2 adrenoceptors (skeletal muscle)
Relaxes vasculature
Parasympathetic// which receptor where?
Heart
M2
Decrease heart rate and force of contrition (atria only)
Parasympathetic// which receptor where?
Lungs
M3
Constrict bronchi and stimulate mucus production
Parasympathetic// which receptor where?
GI tract?
M3
Increases intestinal motility and relaxes sphincters
Parasympathetic// which receptor where?
Adrenal gland
No effect
Parasympathetic// which receptor where?
Bladder
M3
Contract detrusor
NO
Relaxes internal urethral sphincter
Parasympathetic// which receptor where?
Penis
M3 and NO
Penile erection
Parasympathetic// which receptor where?
Vasculature?
Largely no effect
except, penis, salivary glands, pancreas where it relaxes
Explain cholinergic synaptic transmission?
1) Uptake of choline into the cell via choline transporters (rate limiting in ACh synthesis)
2) Synthesis of ACh by choline acetyltransferase (ChAT)
3) Storage of ACh within vesicle via transporter VChAT (ATP and other anions are co stored)
4) Depolarisation of terminal by AP
5) Ca++ influx by voltage activated Ca++ channels
6) Ca++ induced release of ACh into synaptic cleft
7) Activation of ACh receptors causing cellular response
8) Degradation of ACh to choline and acetate by acetylcholinesterase AChE which terminates transmission
9) Uptake and reuse of choline and acetate diffuses out of the synaptic cleft
How is ACh synthesised in the cell?
Acetyl coenzyme A + choline –> Acetylcholine
What is the structure of nicotinic ACh receptors?
5 protein subunits that form a central cation conducting channel
Assembled from a diverse range of subunits. Alpha 1-10, beta 1-4 gamma, delta and epsilon.
What is the structure of nicotinic ACh receptors found in skeletal muscle?
2(alpha1), beta, gamma, epsilon
What is the structure of nicotinic ACh receptors found in ganglia?
2(alpha3), 3(beta4)
What is the structure of nicotinic ACh receptors found in CNS?
5(alpha7) or 2(alpha4), 3(beta2)
What is an epsp?
Excitatory post synaptic potential
A graded depolarisation generated by the infux of Na+ in a post synaptic neurone - amplitude is based on number of ACh receptors
To stimulate and AP the epsp must reach what?
Threshold
Either by multiple preganglionic fibres synapsing at one post ganglionic fibre or repeated stimulation of one preganglionic fibre
Which G protein is activated by M1 receptors and what is the effect?
Gq => stimulation of phospholipase C => increase secretions
Which G protein is activated by M2 receptors and what is the effect?
Gi => inhibition of adenylyl cyclase and opening of K+ channels => decreased heart rate
Which G protein is activated by M3 receptors and what is the effect?
Gq => stimulation of phospholipase C => increase secretions/ contraction of visceral smooth muscle
Which G protein is activated by beta 1 adrenoceptors and what is the effect?
Gs => Stimultion of adenylyl cyclase => increased heart rate and force
Which G protein is activated by beta 2 adrenoceptors and what is the effect?
Gs => stimulation of aadenlyly cyclase => Relaxation of bronchial and vascular smooth muscle
Which G protein is activated by beta 3 adrenoceptors and what is the effect?
Gs => stimulation of adenylyl cyclase => Relaxation of bladder detrusor
Which G protein is activated by alpha 1 adrenoceptors and what is the effect?
Gq => Stimulation of phospholipase C => contraction of vascular smooth muscle
Which G protein is activated by alpha 2 adrenoceptors and what is the effect?
Gi => inhibition of adenylyl cyclase => Inhibition of NA release
There are receptors on both pre and post synaptic neurones at synapses. What are the receptors on presynaptic neurones called?
Autoreceptors
M2 or Alpha 2 receptors
Mediate negative feedback inhibition of neurotransmitter by inhibiting Ca++ entery and opening K+ channel.
If the receptors are stimulated by neurotransmitters than they will decrease further release
What is pharmokinetics?
What the body does to a drug
Absorptions, distribution, metabolism and excretion of drugs and metabolites
What is pharmodynamics?
What a drug does to the body
Biological effect and mechanisms of action
Metabolism + excretion = ?
Elimination
What is a drug?
Any singel synthetic or natural substance of fnown structure used in the prevention, treatment or diagnosis of a disease
What is a medicine?
A chemical preparation containing one or more drugs with the intention of causing a therapeutic effect. Usually contain agents in addition to the active drug eg stabalisers
Drugs bind to target molecules. How are they selective?
Chemical structure of the drug (binding site specificity
Target recognizing ligands of a precise structure (ligand specificity)
Most drugs bind to regulatory proteins. What are these?
What are the none protein targets?
Enzymes, carrier molecules, ion channels, receptors
DNA (anti cancer drugs) and RNA (antibiotics can bind to prokaryotic RNA)
What is an agonist?
A drug that binds to a receptor to produce a cellular response
What is an antagonist?
A drug that blocks the actions of an agonist by binding to the same receptor
What is affinity?
Strength of association between ligand and receptor
What is efficacy?
The ability of an agonist to evoke a cellular response
How is affinity determined?
The the dissociation rate as the rate of binding is almost constant.
By the number or type of chemical bonds a agonist makes with a receptor
Do agonists possess affinity and efficacy?
Yes
Affinity is binding and has 2 rate constants (association and dissociation)
Efficacy is activation and has 2 rate constants (activation and deactivation)
What determines efficacy?
The activation rate as the deactivation rate is similar for all drugs
Do antagonists possess affinity and efficacy?
No just affinity as they do not produce a conformational change- just block the site
Do drugs demonstrate michaelis menton kinetics?
Yes
What is a full agonist?
A drug which can produce a 100% response
Why would you plot concentration against response on a logarithmic axis rather than a linnear axis?
Easier to get an accurate value or EC50 or Km
Compresses the range of concentrations at the upper end and expands them at the low end
What is potency?
Concentration range over which a drug is effective
What is the MEC and MTC?
Minimal effective concentration
Maximal tolerated concentration
What is the therapeutic index?
MTC/MEC
What is the therapeutic window?
The range of plasma concentrations we want the drug to be within
What is first order kinetics?
The rate of elimination is directly proportional to drug concentration. => Drug concentration falls exponentially initially and then the rate of drug leaving the body falls as plasma concentration falls
What is the half life?
The time taken for the plasma concentration to fall by 50%
What is the equation for half life?
t 1/2 = 0.69/Kel
Where Kel is the elimination rate constant
Is the half life constant for a drug with first order kinetics?
Yes
What is clearance?
The volume of plasma cleared of a drug per unit time
only for drugs with first order kinetics
What is the equation for calculating the elimination rate constant?
Kel = Cl x Cp
Where Cl= clearance and Cp = plasma concentration
What determines the maintenance dose rate?
Clearance
What is the point of stready state?
Where rate of drug elimination = rate of drug administration
What is the calculation for the rate of administration (IV) at steady sate?
Cl x (Cp at ss)
How long does it take to reach steady state plasma concentration after administration?
5 half lives
What is oral bioavailability?
The fraction of the drug administered that enters the systemic circulation
What is a loading dose?
AN initial higher concentration of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose
Why is a loading dose used?
To decrease the time to steady state for drugs with a long half life
What is the calculation for a loading dose when giving IV?
LD= Vd x target Cp
Where Vd = volume of distribution
What is the volume of distribution?
The volume in which a drug appears to be distributed with a concentration equal to that of plasma
What is zero order kinetics?
Saturation kinetics where the drug is initially eliminated at a constant rate because the plasma concentration is greater than the rate of metabolism of the enzyme which metabolises it
eg alcohol
Why must you be careful with drugs with zero order kinetics?
Plasma steady state concentration is not linnearly related to dose. Hard to stay within the therapeutic window
What is depolarisation?
The membrane potential becomes less negative.
referring to the excess of charge on the inside of a cell
What is hyperpolarisation?
The membrane potential becomes more negative. referring to the excess of charge on the inside of a cell
WHat drives the passive movement of ions?
electrochemical gradient for the ion
Why does Na+ normally move into the cell?
Concentration gradient is inward and the electrical gradient is inward
When the driving force for Na+ influx is negative, what happens to Na+?
Moves INTO the cell
Vm - ENa+ = -80 - 60 = -140mV
Why does K+ normally move out of the cell?
The concentration gradient is outward and has an energy which EXCEEDS that of the electrical gradient which is inwards
When the driving force for K+ is positive, what happens to K+?
Moves OUT of the cell
Vm - EK+ = -80 - -100 = +20mV
What happens to the membrane potential when:
a) Na+ channels open
b) K+ channels open
a) The membrane potential is driven towards ENa+ (+60mV)
b) The membrane potential is driven towards EK+ (-100mV)
What is ENa+ and EK+?
The equilibrium potential for Na+/K+
What is the threshold potential?
The potential which must be exceeded to generate an action potential (-60mV)
What is the resting potential?
Unexcited state of the membrane (-80mv)
What is the upstroke?
Depolarisation of the membrane
What is the Downstroke?
Hyperpolarisation/repolarisation
What is an action potential?
A brief electrical signal in which the polarity of the nerve cell membrane is momentarily reversed (2 milliseconds)
Do action potentials have a constant magnitude and velocity?
Yes- its axon dependent
What activates voltage gated Na+ and K+ channels?
Membrane depolarisation
Na+ immediately
K+ after a delay
Does activation of Na+ channels follow positive or negative feedback? Explain.
Positive feedback. Depolarisation => Increasing Na+ conductance => greater inward Na+ current => Greater depolarisation
Does activation of K+ channels follow positive or negative feedback? Explain.
Negative feedback.
Depolarisation => Increased K+ conductance => Outward K+ current => repolarisation.
Repolarisation turns the signal for channel opening off
There are two gates within the voltage activated sodium channel. What are these?
Activation gate and the inactivation gate
Following depolarisation what state is the Na+ channel in?
Open conducting state
Both activation gate and inactivation gate are open
Following maintained depolarisation what state is the Na+ channel in?
Inactivated non-conducting state
Inactivation gate is closed but the activation gate is open
Following repolarisation what state is the Na+ channel in?
Closed non conducting state
Activation gate is closed but the inactivation gate is open
What does the inactivation state of the Na+ channel allow?
Repolarisation phase and is responsible for the absolute refractory period
How can the inactivation gate of a Na+ channel be opened?
Repolarisation of the membrane
What is the absolute refractory period?
Where no stimulus, however strong can elicit a second action potential (all Na+ channels are inactivated)
What is the relative refractory period?
Where a stronger than normal stimuli may elicit a second action potential (mixed population of inactivated and closed Na+ channels). The membrane is hyperpolarised so a large depolarisation is required to reach threshold
Why is propagation of a action potential unidirectional?
Refractory period and Na+ channels are inactivated
Why does an action potential decay?
The nerve cell membrane is leaky and not a perfect insulator so passive signals do not spread far from their site of origin due to current loss across the membrane
What is cable therory?
Where current leaks back into the extracellular space across the membrane resistance generating a potential change.
What will increase the leakage of current across the membrane?
Decreasing the membrane resistance and increasing the axon resistance
What is saltatory conduction?
Propagation of action potentials along myelinated neurones from one node of ranvier to the next increasing the AP velocity
What are some demyelinating disorders?
MS (CNS)
Guillian Barre syndrome (PNS) (Reversible)
Both cause slowing/ceasing of nerve conduction
Is axial resistance smaller in wide or narrow APs?
Wide and therefore conduction is faster
Which cells produce myelin in the PNS and CNS?
PNS = schwann cells CNS = Oligodendrocytes
How many schwann cells are needed for each axon of the PNS?
many
How many oligodendrocytes are needed for each axon in the CNS?
One oligodendrocyte can insulate many axons in the CNS
What is absorption?
The process by which a drug enters the body from its site of administration and enters the general circulation
What is distribution?
Transport of a drug by general circulation. Drugs often leave the blood and enter perfused tissue (extracellular fluid, intracellular fluid) Further reversible distribution dictated by a concentration gradient may occur by diffusion or carrier mediated transport
What is metabolism?
The process by which tissue enzymes (mostly liver hepatic metabolism) catalyse the chemical conversion of a lipid soluble drug into a less active and more polar form that is more readily excreted from the body
What is excretion?
Processes that remove the drug or its metabolites from the body. This occurs mostly in the kidneys but can occur through bile (enters GI tract), lactate of females, lungs (ethanol)
What characteristics of a drug can affect its absorption?
1) Solubility- the drug must dissolve in an aqueous solution
2) Chemical stability- not be destroyed by stomach acid or digested by enzymes
3) Lipid to water partition coefficient
4) Degree of ionisation
Which drugs can enter the vascular compartment?
Hydrophilic drugs
Why are some drugs ineffective orally?
Digested in gut or destroyed by stomach acid
Give an example of a drug destroyed by stomach acid and must be given IV?
Benzylpenicillin
Give an example of a drug digested by enzymes and must be given IM?
Insulin
In IBS treatment the drug is inactive in the small intestine but active in the colon. How is this?
Drug is modified by the GI tract. Bacteria in the colon activate the drug.
What is the lipid to water partition coefficient?
The ratio of the drug concentration is the membrane and concentration in water a equilibrium.
Eg a partition coefficient of 4 means the drug is 4 times more concentrated in the membrane than water. Good for diffusion across the lipid membrane
What is the ionised form of an acid and a base?
Acid A-
Base BH+
WHat is the unionised form of an acid and a base?
Acid HA
Base B
Onle ionised/unionised forms of a drug will diffuse across a biilayer?
Unionised
What does the degree of ionisation depend on?
pKa of the drug and the pH of the environment
When does pH = pKa?
At equilibrium, when half the drug is ionised and half the drug is not?
Give an example of an acidic drug?
Asprin pKa = 3.4
What equations can be used to calculate the proportions of drugs ionised?
Henderson hasselback equestions
See workshop sheets
An acidic drug will ionise more/less in an acidic pH but will ionise less/more in a basic pH.
Less in acid
More in base
An basic drug will ionise more/less in an acidic pH but will ionise less/more in a basic pH.
more in acid
Less in base
Where are acidic and basic drugs absorbed?
Acidic = stomach
Basic = small intestine
NB: most absorption, even of weak acids occurs in the intestine
Weak acids and bases are better absorbed than strong acids and bases. T or F?
True
What GI factors can affect absorption?
1) GI motility- rate of stomach emptying (increases with food)
2) pH at absorption site
3) Blood flow to stomch and intestine
4) Physiochemical interactions- rate of some drug absorption is altered by Ca++ rich foods
5) Transporters (in epithilial membranes that facilitate drug absorption
6) Tablet manufacture- release drugs at different sites/rates
What is oral availability?
The fraction of the drug that reaches the systemic circulation after oral ingestion
Oral availability = amount in systemic circulation / amount administered
What is systemic availability?
The amount of a drug that reaches the systemic circulation after absorption
Systemic availability = amount in systemic circulation / amount absorbed
Why do IV drugs have a 100% systemic availability?
Bypass liver/ first pass metabolism
What is first pass metabolism/presystemic metabolism?
The modification/destruction of someoral drugs by the liver and gut wall enzymes
What is an entral route?
A drug which is swallowed and enters the GI tract
Give 3 entral routes of drug administration?
PO- oral
SL- buccal or sublingual = Drug is absorbed into the blood
PR- Rectal = aviods some first pass metabolism and good for slow release is vomiting/fitting
What is the paraentral route?
Not via the GI tract
Give 6 examples of paraentral route administration?
IV, IM, SC, INH, TOP, Transdermal
What are the advantages and disadvantages of IV administration?
\+ 100% systemic availability \+ Rapid onset \+ Continuous infusion - Embolism - Sterile site/infection - High drug levels at heart
What are the advantages and disadvantages of IM administration?
+ depo injection for slow release
+ Rapid onset of lipid soluble drugs
- Absorption dependent onmuscular perfusion
- Painful tissue damage
What are the advantages and disadvantages of transdermal administration?
+ slow absorption across skin
- Local irritation possible
What are the 5 fluid compartments of the body?
Plasma water, interstitial water, intracellular water, transcellular water (CSF, synovial fluid), Fat
Only free/bound drugs can move between compartments?
Free
Where can both ionised and unionised drugs move by diffusion?
From plasma water to interstitial water only. To get further only unionised drugs move by diffusion
Are drugs evenly distributed in the body?
No
What is the calculation for Vd?
Vd = amount of drug in body / plasma concentration
What does a Vd imply?
a) <10L
b) 10-30L
c) >30L
a) Drug is largely retained in vascular compartment (too large or bound to plasma proteins)
b) Drug largely restricted to extracellular fluid (low lipid solubility)
c) Distribution throughout body water, accumulation in cirtain tissues or bound to tissue proteins
To perfuse the CNS what must a drug be?
highly lipid soluble
What is autocrine signaling?
Signaling molecules released by signaling cell bind to receptors on signaling cell to generate a response
What is paracrine signaling?
Signaling molecules released by signaling cell bind to receptors on nearby or adjacent target cells = response
What is endocrine signaling?
Signaling molecules released by signaling centre enter circulation and travel to another body region to target cells => response
What type of signaling is neuronal communication?
Specialist form of paracrine signaling
What are the 4 major classes of receptor?
1) Ligand gated ion channels (ionotraphic)
2) GPCR (metabotrophic)
3) Kinase linked (linked to the addition of phosphate)
4) Nuclear
Where are nuclear receptors located?
Plasma membrane, intracellular membrane (ER), cytoplasm or nucleus (hydrophobic molecules)
What molecules target kinase linked receptors?
Hydrophilic mediators eg insulin and growth factors
What forms ion channels?
Transmembrane pore formed by gylcoproteins which span the membrane
How are ion channels gated?
CHemical signals = ligand gated ion channels
Transmembrane voltage = voltage gated
Physical and mechanical stimuli = thermal and mechanical energy
What are the 3 categories of ligand gated ion channel based on protein sub unit assembly?
Trimeric (3 subunits, 2 membrane spans)
Tetrameric (4 subunits, 3 membrane spans)
Pentameric (5 subunits, 4 membrane spans)
How many binding sites on a nicotinic receptor?
2 and both must be filled for the ion channel to open effectively
What is a second messenger?
Water soluble signaling molocule which moves from the periphery to the centre of a cell to intracellular targets
What is the structure of a GPCR?
SIngle polypeptide with intracellular NH2 and intracellular COOH termini.
7 transmembrane spans with 3 intra and 3 extracellular loops
What is the structure of a G protein?
Guarrine nucleotide binding protein
Peripheral membrane protein with 3 polypeptide subunits (alpha, beta and gamma)
Exist in 3 types named according to alpha subunit
Where is the guarnine nucleotide binding site in the G protein?
Alpha sub unit which holds GTP or GDP
How are G proteins activated?
1) agonist binds to GPCR
2) In inactive state, beta and gamma paired to form a sub unit, GDP in alpha subunit, both attached covelently to the membrane
3) Alpha subunit contains GTPase domain with Ras and AH sub domains. Ras is the GTPase and AH clamps the nucleotide in place
4) GPCR undergoes a conformational change and G protein can bind causing a chage in alpha subunits
5) GDP is releases and GTP binds (guarnine nucleotide exchange)
6) Alpha subunit separates from receptor and beta/gamma dimer subunit dissociation
7) Generates a free GTP bound alpha subunit and a beta/gamma dimer that can signal
How is the G protein signal switched off?
NB: the agonist may dissociate from the GPCR but the signal can continue
1) alpha subunit enzyme GTPase hydrolyses GTP and the signal is turned off
2) G protein alpha sub unit recombines with beta/gamma subunit completing the G protein cycle
How do Gs and Gi proteins work?
Gs stimulates and Gi inhibits adenylyl cyclase.
Andenylyl cyclase converts ATP to cAMP which is a second messenger activating Protein kinase A in the cytoplasm which can phosphorylate other proteins for a cellular effect
How does Gq protein work?
Gq activates phospholipase C
Phospholipase C converts PIP2 to IP3 and DAG (second messengers)
IP3 diffuses into the cytoplasm and binds to a receptor on the ER or SR => muscle contraction
DAG activates Protein kinase C => Phosphorylation of Ser/Thr residues and cellular effects
How does insulin signal?
Receptor kinase unbound = 2 alpha and 2 beta subunits held by disulphide bonds
Binding of insulin causes autophosphorylation of intracellular tyrosine residues
=> Recruitment of multiple adapter proteins that are tyrosine phosphorylated
=> cellular effects- incorporation of glucose transporterd in the membrane to allow glucose absorption into the cell
How does nuclear signaling work?
1) Steroid hormones enter cell by diffusion
2) Bind to an intracellular receptor producing dissociation of inhibitory HSP proteins
3) Receptor steriod complex moves into the nucleus and forms a dimer than binds to hormone response elements in DNA
4) Transcription of specific genes is transactivated or transrepressed to alter mRNA levels in the cell
What is a nuclear receptor?
Ligand gated transcriptional factor
Where are steroid and thyroid hormone receptors found?
Steroid = cytoplasm Thyroid = nucleus
What is the slowest and fastest form of signaling?
Nuclear receptors slowest
Ligand gated ion channels fastest
