Ch 7: Acetylcholine

ACh Synthesis Pathway

Choline → Acetyl CoA —ChAT—> Acetylcholine → Coenzyme A

Precursor availability and cell firing rate

Synthesis depends on

VAChT

Vesicular ACh transporters, blocked by vesamicol

Botulism Toxins (Botox)

A-G produced by clostridium botulinum

AChE breaks down ACh to

Choline and acetic acid

3 Forms of AChE

Soluble, Membrane bound, A12 Neuromuscular junction

AChE

Prevents breakdown of ACh, prolongs ACh action at synapses

HC-3

Blocks choline transporters

Knockout Choline Transporters

Mice died within one hour

How many subunits form tetramer (G4)?

4

Reversible ACh Inhibitors

Aricept, Exelon, Reminyl

Eserine

Reversible AChE inhibitor, used for glaucoma

Organophosphorus Compounds

Irreversible AcHe inhibitor, used as insecticides

Myasthenia Gravis

Autoimmune condition where antibodies against muscle cholergic receptors are produced

How Myasthenia Gravis is Treated

Prostigmin and Mestinon, don’t cross BBB

Decreased ChAT

Not enough ACh is released at the neuromuscular junction

Decreased AChE

Increased ACh levels lead to receptor desensitization, and decreased transmission

Movement regulation in striatum depends on

ACh and DA balance

Basal Forebrain Cholingeric System (BFCS)

Origin of cholinergic distribution of the cerebral cortex, hippocampus, limbic system

Projections from Medial Septum to Hippocampus

Encodes declarative memories

Projections from Nucleus Basalis to PFC

Important for sustained attention

Optogenetic Experiments in Mice

Bursts of ACh released are key in detecting/responding to sensory cues

Nicotinc Receptors

Respond to agonist nicotine, excitatory, ionotropic

Mecamylamine

Antagonist at nAChRs, antihyperintensive agent, CNS & automatic ganglia

D-tubocurarine

Muscle nAChR antagonist, paralyzes, main active ingredient in curare

Neonicitoids

Imidacloprid, acetamiprid, thiacloprid

Muscarinic Receptors

Respond to agonist muscarine, metabotropic, parasympathomimetic

M1, M3, M5

Excitatory, activates phosphoinositide 2nd messenger system

M2, M4

Inhibitory, inhibits cAMP synthesis and Ca2+ opening, stimulates K+ opening

M5 Knockout Mice

Deficits in morphine/cocaine reward

Cardiac Muscle

M2 Receptors, PNS stimulation slows heart rate

Smooth Muscle/Secretory Glands

M3 Receptors, contraction and increased secretory activity

Natural Muscarinic Agonists

Muscarine, locarpine, arecoline

Muscarinic Poisoning

Exaggerated PNS symptoms