Lecture 6 Flashcards by Teruka Taketa

What are ligand-gated ion channels involved in?

Fast synaptic transmission (microseconds - millisecond)

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What are endogenous ligands?

Fast/classical neurotransmitters

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What are examples of neurotransmitters?

glutamate, ACh

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How many subunits are in ligand-gated ion channels?

3-5

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How many transmembrane spanning domains are in each subunit?

2-4

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How is the complex arranged to form?

a central aqueous pore

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What are structural features of ligand-gated ion channel families?

cys-loop structure
many distinct nicotinic receptors
many, many distinct GABAa receptors
two distinct 5-HT3 receptors (Nicotinic-5 domains)
two distinct glycine receptors

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What are three main classes of ligand gated ion channels?

nicotinic ACh receptor
glutamate receptor
P2X receptor

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What is an example of a ligand-gated ion channel?

nAChR

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Where is nAChR found?

Neuromuscular junction, CNS, PNS

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What is the agonist for nAChR?

nicotine

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What is the antagonist for nAChR?

tubocuranine (nicotinic receptors blocked in neuromuscular junction) can lead to asphyxiation

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What does the activation of ionotropic receptors for inhibitory neurotransmitters lead to?

Inhibit membrane depolarization

Reduce action potential firing

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What is an example of an activation of ionotropic receptors for inhibitory neurotransmitters?

GABAaR

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Where is the GABAaR found?

brain

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What are agonists for GABAaR?

GABA, phenobarbitone

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What is an antagonist for GABAaR?

Picrotoxin

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What is phenobarbitone used for?

euthenasia

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What does phenobarbitone do?

Opens all inhibitory GABA receptors in brain to inhibit CNS activity which can lead to a coma which leads to death

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What can picrotoxin lead to?

Excitation and inhibition
convulsion
epileptic seizures

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What are examples of endogenous ligands?

vasopressin, angiotensin

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What is an example of neuropeptides?

opioids

What are examples of small molecule transmitters?

ACh, nonadrenaline, histamine

What are examples of metabolic receptors?

mAChRs, adrenoceptors, opioid receptors

How many times does the receptor polypeptide span the membrane?

7 times

Is it formed from multiple subunits?

What protein does it use to regulate effector proteins?

G proteins

What does a G protein generate?

Second messenger

Are signals by G protein coupled receptors long-lasting or short?

Long

What sort of processes are G protein coupled receptors involved in?

gene transcription

Are G proteins heterotrimeric or homotrimeric?

heterotrimeric

What are G proteins?

Proteins that bind guanine nucleotides (GDP at rest and GTP when activated)

What are the three subunits of G-proteins?

alpha, beta, gamma

Which subunits split when activated?

alpha, beta-gamma

What does it mean when the subunits dissociate and the receptor is free?

The receptor is free to activate more G proteins for amplification

How many major families of G-protein alpha-subunits are there?

What does Gs(alpha) do?

Increase AC activity and cholera toxin sensitive

What do Gi1(alpha), Gi2(alpha), Gi3(alpha), Go(alpha) do?

Increase AC activity and is pertussis toxin sensitive | The beta-gamma subunits bind directly to Ca and K subunits

What do Gt1(alpha), and Gt2(alpha) do?

Initiate cG phosphodiesterase cascade (visual transduction)

What does PLC activate?

PKC

What does Gq(alpha) activate?

PKC and PLC

What effectors are regulated by G protein coupled receptors (GPCRs?)

enzymes which regulate levels of second messengers | ion channels

What are examples which regulate levels of second messengers?

Gs : increases adenylyl cyclase and cAMP Gi : decreases adenylyl cyclase and cAMP Gq : increases PLC, IP3 and intracellular calcium

Can single GPCRs regulate multiple effectors?

yes

Can multiple GPCRs couple to a single effector?

yes

Is there cross-talk between receptors?

yes

_ of extracellular changes

intracellular coding

What are examples of GPCRs involved in the regulation of catecholamine in the cardiovascular system?

beta-1 adrenoceptors, positive ionotropic and chronotropic effects in the heart alpha-2 adrenoceptors, presynaptic inhibition of NA release

What can adrenoceptor agonists be used for in the cardiovascular system?

Adrenaline - cardiac arrest adrenaline - anaphylaxis Clonidine - hypertension

What can adrenoceptor agonists be used for in the respiratory system?

Salbutamol (beta-2 selective) - bronchodilator | Ephedrine (beta agonist indirectly acting sympathomimetic drug which causes NA release) - nasal decongestant

What are clinical uses for adrenoceptor antagonists?

prazosin (alpha 1 selective) - hypertension carvedilol (alpha and beta) - heart failure Propanolol (beta 1 and beta 2) - anxiety (somatic symptoms)

What are unwanted effects from adrenoceptor antagonists?

``` bronchoconstriction cardiac depression (elderly) bradycardia fatigue cold extremities ```

How can drugs act indirectly to enhance cholinergic transmission?

Inhibits cholinesterase e.g. acetylcholinesterase (AChE) CSF, synaptic cleft at cholinergic synapses and cholinergic nerve terminals

How are anticholinesterease drugs classified by duration of action?

``` Short acting (reversible binding): edrophonium Medium (slow hydrolysis): neostigmine and pyridostigmine (MG don't cross BBB), physostigmine (crosses BBB - used topically for glaucome) Long (irreversible): nerve gas, organophosphates, pesticides (crosses BBB) ```