Pharmacology of cholinergic transmission Flashcards
Two types of receptors for ACh?
Nicotinic
Muscarinic
Subunit composition of nicotinic muscle receptor subtype
(α1)2β1,δ,ε
Where is the nicotinic receptor found in the muscle?
at the skeletal neuromuscular junction
What agonists act on the nicotinic receptor of NMJ?
ACh, nicotine (weak), suxamethonium
Antagonists that act on nicotinic receptor of NMJ?
Pancuronium, tubocurarine
Subunit composition of the ganglionic subtype receptor
(α3)2(β4)3
Where is this ganglion found?
autonomic ganglia
Subunit compoisiton of CNS subtype of the nicotinic receptor
α4)2(β2)3 or (α7)5
found in the brain
Agonists and antagonists act on the nicotinic receptor in the ganglia and brain?
agonists: ACh, nicotine, DMPP
(dimethylphenylpiperazinium)
antagonists: hexamethonium, trimetaphan
Structure of muscarinic receptors?
- metabotropic, G-protein coupled receptors
- single protein molecule of 400-1000 amino acids
- 7 transmembrane spanning domains
- extracellular N-terminus
- 5 molecular subtypes of MAChR
Where are M3 receptors found in the body?
- pupil constriction
- ciliary muscle contraction
- lacrimal gland & salivary gland- increased secretion
- airway smooth muscle- bronchoconstriction
- exocrine glands- secretion
- smooth muscle contraction in upper GI tract- increase in motility
- dilation of sphincters in upper GI tract
- gland secretion in upper GI tract
- smooth muscle contraction of bladder
- dilation of blood vessels in genitalia
Where are M2 receptors found?
- in SA node to decrease heart rate
- in AV node to decrease conduction velocity
(no effect on ventricular muscle)
Location and action of M1 receptors
Gastric acid secretion in upper GI tract
describe M1 muscarinic receptors
- GPCR
- found in CNS, enterochromaffin cells in the stomach to regulate gastric acid secretion
- when activated: activation of PLC/IP3/DAG signalling leading to closure of potassium channels
- effects include gastric acid secretion and nerve cell excitation
explain the PLC/IP3/DAG signalling pathway
PLC- phospholipase C
IP3- inositol 1,45 triphosphate
DAG- diacylglycerol
PIP2
M1 receptor activation by acetylcholine
beta and gamma subunits leave producing the active form of the receptr
Phospholipase
C catalyses the hydrolysis of the phospholipid PIP2
Results in formation of IP3- stimulates release of calcium and activation of calcium dependent responses e.g. smooth muscle contraction
DAG is formed which stimulates protein kinase C
phosphorylation of target proteins
Action of M2 receptors
- GPCR
- found in CNS and pacemaker cells (AVN, SA)
- cellular response- reduction in heart rate and reduction in conduction velocity
- inhibition of adenyl cyclase (AC) leading to reduced levels of cAMP and opening of potassium ion channels
- key effects- decreased heart rate, nerve cell inhibition
adenylyl cyclase- cAMP signallng pathway
stimulation of adneylyl cyclase
causes ATP to converto cAMP
cAMP activates protein kinase A
phosphorylation of targtet proteins
Gs protein (beta adrenoreceptor) stimulates adenylyl cyclase
Gi protein (M2 receptor) inhibits adenylyl cyclase
Action of M3 receptors
- GPCR
- found widespread throughout the body on smooth muscle in GI tract, airways, secretory glands and bladder
- cellular response when activated- activation of PLC/IP3/DAG signalling pathway leading to closure of potassium channels
- leading to bronchoconstriction, increased GI motility, galnd secretion, bladder emptying, contraction of ciliary muscle and pupil constriiction
What drugs affect ganglia?
nicotinic receptor agonists and antagonists
Nicotinic receptor agonists
ganglion stimulants
preferentially activate nicotinic receptors in autonomic ganglia
e.g. nicotine, lobeline, DMPP
no clinical use
CNS and peripheral effects of nicotine
CNS effects
Drug dependence and tolerance due to complex action of nicotine on nicotinic receptors in the CNS ((α4)2(β2)3 subtype
• Increased alertness
• Arousal
• Enhanced learning
• Reduced anxiety and tension
Peripheral effects
• Tachycardia; increased cardiac output, BP
• Reduced GI motility
• Sweating
• Nausea and vomiting for first time smokers
• Tolerance develops to peripheral effects
Harmful effects of smoking
• Cancer, coronary artery disease, emphysema
Nicotinic receptor antagonists
- Also called ganglion blockers
- Used experimentally but only rarely clinically
- Examples include hexamethonium and trimetaphan
- Major effect of ganglion blockers is a reduction in blood pressure (postural hypotension upon standing)
- Mainly side effects- ‘hexamethonium man’
- Trimetaphan used clinically to reduce bleeding during surgery
Muscarinic receptor agonists
- Also called parasympathomimetics
- Activate muscarinic receptors but NOT nicotinic receptors and include pilocarpine and bethanacol
- Limited clinical use because they show little selectively between muscarinic receptor subtypes
- Pilocarpine eyed drops are used in treatment of glaucoma (pin point pupil and ciliary muscle spasm are side effects)
- Bethanacol is used as a stimulant laxative and to treat urinary retention
What are the parasympathomimetic effects of pilocarpine in gluacome?
- Contraction of constrictor muscle (M3 receptors): pupil constriction (miosis)
- Contraction of ciliary muscle (M3 receptors): suspensory ligaments lose tension and then lens adopts a fatter, spherical shape to accommodate for near vision
Contraction of ciliary muscle; improves aqueous humour flow reducing intraocular pressure (IOP)
