DBM - Chapter 7 - Acetylcholine

ACh synthesis

choline + acetyl CoA → choline acetyltransferase (ChAT) → acetylcholine + coA

ChAT ONLY found in neurons that use ACh as their neurotransmitter

rate of synthesis: availability of precursors, rate of cell firing

VAChT (vesicular acetylcholine transporter)

moves ACh into synaptic vesicles

blocked by vesamicol → reduces ACh released

LTX (black widow spider venom, larotoxin)

toxin that causes massive release of ACh in the PNS

muscle pain, tremors, nausea, vomiting, increased salivation and sweating

mechanisms of action:

1. neurexins on neuronal membrane → insertion of ⍺-LTX, Ca²⁺ influx

2. latrophilin stimulated by ⍺-LTX

botulinum toxin (botox)

bacterial toxin, blocks ACh release at NMJ

most potent toxin, causes muscle paralysis

acetylcholinesterase (AChE)

breaks ACh down into choline and acetic

• in presynaptic cell: can metabolize excess ACh that has been synthesized

• on postsynaptic membrane: breaks down ACh after release into cleft

G4 AChE

form of AChE synthesized in cholinergic neurons and neurons that receive ACh input

• most is bound to cell membrane by a tail

A12 AChE

form of AChE synthesized at the NMJ

• collagen tail anchors to extracellular matrix

• ACh broken down rapidly so muscle can relax before contraction

choline transporters

uptakes choline into nerve terminal

recycled choline → critical in maintaining ACh synthesis

no ACh transporters

anticholinesterases

AChE inhibitors

ACh accumulation and overstimulation of cholinergic synapses in both the CNS and PNS

• muscle paralysis and death by asphyxiation

myasthenia gravis

autoimmune disorder

body makes antibodies against ACh receptors at the NMJ

treated with reversible inhibitors that do not cross the BBB

nicotinic ACh receptors (nAChR)

found in autonomic ganglia

• in both sympathetic and parasympathetic

• highly concentrated at NMJ

ionotropic; respond to agonist nicotine

mediate fast excitatory responses

pentamers

muscarinic ACh receptors (mAChR)

found in target organs

• more widely distributed and common than nAChRs

parasympathetic, except for sweat glands

metabotropic; respond to agonist muscarine

major receptor of postganglionic ACh in parasympathetic

cholinergic cell bodies

clustered in a few areas in the CNS

basal forebrain cholinergic system (BFCS)

• origin of dense cholinergic innervation of the cerebral cortex, hippocampus, limbic system

dorsolateral pons

• some have excitatory influence on midbrain DA neuron firing

functional states of nicotinic receptors

1. open

2. closed

3. desensitized ***not all receptors

   1. continuous agonist exposure

   2. channel remains closed even when agonist is bound

succinylcholine

powerful muscle relaxant used in surgery

resistant to AChE breakdown

produces persistent depolarization, depolarization block

varenicline (Chantix)

partial agonist at high-affinity ⍺4β2 nicotinic receptors expressed in the VTA

⍺7 agonists

⍺7 highly expressed in cognition and memory regions

stimulation of ⍺7 receptors improves attention and cognition

significant reduction of ⍺7 in hippocampus in Alzheimer’s and schizophrenia

mAChR subtypes

5 subtypes: M1-M5

• M1, M3, M5: activate PLC (Gq)

• M2, M4: inhibit AC (Gi)

  • also open K+ channels

  • effect dependent on cell type

M5 receptors in brain

receptor subtype expressed in hippocampus, hypothalamus, midbrain DA

• leads to enhanced DA release in NA

M5 receptors in drug abuse

M5 KO mice exhibit deficits in morphine and cocaine reward

• still show morphine induced analgesia

• only affects reward pathway, not analgesic pathway

• M5 antagonists to treat addiction?

M5 muscarinic receptor negative allosteric modulator (ML375)

reduces voluntary ethanol consumption

xanomeline-trospium (KarXT)

muscarinic agonist and muscarinic antagonist

• preferentially stimulate muscarinic receptors in the CNS

• does not rely on DA or 5-HT pathways