Lecture 6 Flashcards
What are ligand-gated ion channels involved in?
Fast synaptic transmission (microseconds - millisecond)
What are endogenous ligands?
Fast/classical neurotransmitters
What are examples of neurotransmitters?
glutamate, ACh
How many subunits are in ligand-gated ion channels?
3-5
How many transmembrane spanning domains are in each subunit?
2-4
How is the complex arranged to form?
a central aqueous pore
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
What are three main classes of ligand gated ion channels?
- nicotinic ACh receptor
- glutamate receptor
- P2X receptor
What is an example of a ligand-gated ion channel?
nAChR
Where is nAChR found?
Neuromuscular junction, CNS, PNS
What is the agonist for nAChR?
nicotine
What is the antagonist for nAChR?
tubocuranine (nicotinic receptors blocked in neuromuscular junction) can lead to asphyxiation
What does the activation of ionotropic receptors for inhibitory neurotransmitters lead to?
Inhibit membrane depolarization
Reduce action potential firing
What is an example of an activation of ionotropic receptors for inhibitory neurotransmitters?
GABAaR
Where is the GABAaR found?
brain
What are agonists for GABAaR?
GABA, phenobarbitone
What is an antagonist for GABAaR?
Picrotoxin
What is phenobarbitone used for?
euthenasia
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
What can picrotoxin lead to?
Excitation and inhibition
convulsion
epileptic seizures
What are examples of endogenous ligands?
vasopressin, angiotensin
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?
no
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?
4
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)
