Cholinergic Transmission

What are the two types of receptor for ACh?

Nicotinic and muscarinic

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Describe features of nicotinic receptor subtypes

5 sub units surrounded by ion channel. Located in skeletal NMJ. Agonists - ACh, nicotine, suxamethonium. Antagonists - tubocurarine, pancuronium

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Describe features of muscarinic AChR

G-protein coupled receptors - heptahelical protein, N-terminus outside, C-terminus inside (there are 5 subtypes M1-M5)

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The majority of muscarinic receptors in the parasympathetic system are what?

M3

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What is the receptor for the heart in the parasympathetic system?

M2

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What is the receptor for gastric acid secretion in the parasympathetic system?

M1

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Describe features of M1 receptors

GPCR. Found in CNS, enterochromaffin like cells in stomach wall. Activation of PLC/IP3/DAG signalling (close K channels). Gastric acid secretion, nerve cell excitation

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Describe the PLC/IP3/DAG signalling pathway (1)

ACh binds to M1 receptor (Gq protein). Beta/gamma sub units drop. Alpha bound to M1. Activation of phospholipase C (break down PIP2, produce IP3). Release Ca2+ from stores, increase Ca 2+

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Describe the PLC/IP3/DAG signalling pathway (2)

Other pathway - DAG stays in membrane, activates second enzyme (protein kinase C) - phosphorylation of target proteins

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Describe features of M2 receptors

GPCR. CNS, pacemaker cells of heart (SA and AN node). Inhibition of adenyl cyclase (AC) leading to reduced levels of cAMP (open K channels). Decreased heart rate, nerve cell inhibition

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Describe the adenylyl cyclase - cAMP signalling pathway (parasympathetic)

ACh binds to M2 (Gi protein). Beta/gamma drop off alpha activated. Inhibits adenylyl cyclase, less cAMP, less protein kinase A, less phosphorylation of target proteins

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Describe the adenylyl cyclase - cAMP signalling pathway (sympathetic)

Beta adrenoreceptor (Gs protein). Beta/gamma drop off alpha activated. Stimulates adenylyl cyclase, more cAMP (from ATP), more protein kinase A, more phosphorylation of target proteins

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Describe features of M3 receptors

GPCR. In smooth muscle e.g. GI tract, airways, bladder, secretory gland. Activation of PLC/IP3/DAG signalling (close K channels). Bronchconstriction, increased GI motility, bladder emptying, contraction of ciliary muscle, pupil constriction

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Describe features of drugs which affect ganglia - NAChR

Ganglion stimulants. Agonists which preferentially activate nicotinic receptors in autonomic ganglia. Nicotine, lobeline, DMPP - no clinical use

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Describe the CNS effects of nicotine

Drug dependence and tolerance due to complex action of nicotine on NAChR - increase alertness, arousal, enhanced learning, reduced anxiety and tension

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Describe the PNS effects of nicotine

Tachycardia, increase CO/BP. Reduced GI motility, sweating, nausea, vomiting for first time smokers, tolerance develops to peripheral effects

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What are the harmful effects of smoking?

Cancer, coronary artery disease, emphysema

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Describe features of drugs affecting ganglia - neuronal nicotinic receptor antagonists

Ganglion blockers. Used experimentally (rarely clinically). E.g. hexamethonium and trimetaphan. Reduced BP. Side effect - hexamethonium man. Trimetaphan used to reduced bleeding in surgery

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Describe features of muscarinic receptors - muscarinic receptor antagonists

Parasympathomimetics. Activate muscarinic receptors but not nicotinic receptors and include pilocarpine/bethanacol. Little selectivity. Treatment of glaucoma. Treatment of urinary retention

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What are the parasympathetic effects on the eye?

Contraction of constrictor muscle (M3), pupil constriction. Contraction of ciliary muscle (M3), suspensory ligaments lose tension and lens adopts a fatter spherical shape to accommodate for near vision

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What does contraction of ciliary muscle improve?

Aqueous humour flow reducing intraocular pressure

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Describe features parasympatholytics and anti-cholinergics

Diltation of pupil, paralysis of ciliary muscle, increased intraocular pressure. Dry mouth/skin, increase in body temp. Tachycardia. Bronchodilation. High doses inhibit gastric motility/acid secretion. Urinary retention. CNS excitation (agitation)

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What are the clinical uses of musarinic receptor antagonists?

Sinus bradycardia, dilate pupil, treat asthma and COPD, IBS, urinary incontinence, motion sickness, Parkinson's disease

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Describe features of AChE

Hydrolyses ACh. Soluble form of enzyme found in nerve terminals, erythrocytes, CSF. BChE found in blood plasma and tissues (hydrolysis procaine)

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Describe features of AChE inhibitors

Prevent breakdown of ACh. Different drugs have different durations (due to strength of bonds)

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Describe the actions of AChE drugs

Parasympathomimetic. Increase secretions, smooth muscle tone, mitosis etc.

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What happens when high doses of AChE drugs are used?

Depolarising block of synaptic transmission at autonomic ganglia can occur

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What readily penetrates the BBB?

Tertiary AChE inhibitors and non-polar organophosphates. Produced initial excitation, followed by convulsion and depression, unconsciousness and respiratory failure

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What are the clinical uses of AChE drugs

Reverse effects of non-depolarising muscle relaxants. Used in diagnosis and treatment of mysaethenai gravis. Used in eye drops to treat glaucoma

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What is believed to account for the learning and memory deficits in Alzheimer's disease?

Loss of cholinergic neurones with ageing - AChE inhibitors shown to be some benefit in treating early stages of AD

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Cholinergic Transmission

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