Acetylcholine
From Medical-Wiki
Acetylcholine is one of the major neurotransmitters in the mammalian nervous system, found at all neuromuscular junctions, at all synapses in autonomic ganglia, at a variety of locations in the CNS and peripheral end organs.
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Acetylcholine Synthesis
Acetylcholine is synthesized from a choline precursor and an acetyl group providing by Acetyl CoA (a cofactor). Choline acetyltransferase (ChAT) is the enzyme that catalyzes the synthesis, and staining for ChAT is regularly used to identify cholinergic neurons. Cholinergic neurons also have an Na+/Choline cotransporter that drives choline into the neuron.
Acetylcholine Clearance
Acetylcholine is quickly cleared from the synaptic terminal by acetylcholinesterase. This enzyme is found in high concentrations at the NMJ and other cholinergic synapses. Ach is degraded into an acetyl group and choline. The choline can then reenter the neuron through the Na/Choline cotransport.
Acetylcholine Receptor Types
Nicotinic Ach Receptors
Nicotinic Ach R are broadly classified into 3 types: NMJ, CNS, and preganglionic. All are ionotropic receptors. Despite these three “classes” there are actually many varieties of nAchRs because each receptor is made up of about 15 subunits, with variants for most of the subunits.
Muscarinic Ach Receptors
Muscarinic Ach R are found in neurons, cardiac muscles, and glandular end organs. Again, despite these three general locations for mAchRs, there are least 5 classes (m1-m5), found at different locations.
Cholinergic synapses in the peripheral nervous system
All preganglionic neurons in the autonomic nervous system (both sympathetic and parasympathetic) release Ach.
All postganglionic neurons in the ANS have nicotinic Ach receptors, so the main communication between preganglionic and postganglionic neurons in the ANS is via nicotinic Ach receptors. As a result, anything that activates (eg. Nicotine) or blocks (eg. Hexamethonium) nicotinic receptors can affect on both the para- and sympathetic systems, and the results are therefore “mixed” looking.
Postganglionic neurons in the parasympathetic system release Ach. End organs have muscarinic receptors. The action of agonists and antagonists depends on the site.
Ach is the neurotransmitter found at the neuromuscular junction, so normal Ach neurotransmission is a requirement for movement.
Cholinergic synapses in the central nervous system
The major cholinergic nucleus in the human brain is found in the basal forebrain (the Basal Nucleus of Meynert). This nucleus projects widely to the cerebral cortex, and cholinergic tone is thought to affect the degree to which neurons in the cerebral cortex are synchronized.
Acetylcholine pharmacology
Nicotinic receptor antagonists
Antagonists of the nicotinic Ach receptor suppress muscle activity. Clinically this is seen in many situations: curare (and other agents like pancuronium) produces a “non-depolarizing” muscle block by antagonizing the nAchR at the NMJ. Increasing the Ach concentrations at the NMJ can reverse these effects, so acetylcholinesterase inhibitors (like neostigmine or edrophonium) can be used to reverse muscle block in myasthenia gravis and curare poisoning (although it will not necessarily be a complete or long-lasting reversal).
Nicotinic receptor agonists
Agonists that activate nAchR can paradoxically block muscular activity – prolonged activation (for example in the presence of constant succinylcholine, which cannot be hydrolyzed by acetylcholinesterase) depolarizes the muscle, pushing Na channels to inactivation. The muscle can no longer contract despite open nAchR at the NMJ because the Na+ channels will not pass current to depolarize the muscle past threshold. This is known as “depolarizing block” and succinylcholine is often used as a muscle relaxant to allow intubation.
Muscarinic receptor antagonists
Muscarinic antagonists block many parasympathetic functions. For example, atropine (a musc. antagonist) blocks action at the pupillary sphincter, causing dilation. Recall that the light reflex acts through the Edinger-Westphal nucleus which sends parasympathetic preganglionic fibers to the ciliary gaglion (so nicotinic Ach receptors in the ganglion), and the ciliary ganglion sends fibers to the pupillary sphincter (so muscarinic Ach receptors). Topical atropine blocks the musc Ach receptor at the sphincter, preventing parasympathetic input from constricting the input, so the pupil dilates.
The same mechanism is found at other end organs, for example atropine also affects cardiac function, blocking the bradycardia and vasodilation that the paraysmpathetic system induces; this results in tachycardia and elevated blood pressure.
Muscarinic receptor agonists
Muscarinic agonists can have the opposite effect. See Glaucoma discussion below.
Acetylcholinesterase inhibitors
Acetylcholinesterase inhibitors slow the degradation of Ach at the synapse and therefore increase the concentration (by increasing half-life) of Ach in the synapse. Short and medium duration acting inhibitors are useful clinically. Edrophonium is short acting and is sometimes used to confirm a diagnosis of myasthenia gravis.
High yield clinical issues relating to acetylcholine and Ach Receptors
Myasthenia Gravis
In myasthenia gravis there are antibodies to nicotinic Ach receptors, so over the course of a day the nAchR in the NMJ get blocked and movement becomes sluggish. Acetylcholinesterase inhibitors, that slow the degradation of Ach therefore increasing the Ach concentration in at the NMJ, is a good treatment. Thymectomy is often curative, although the mechanism of cure is not well understood.
Botulinum Toxin (botox)
Ach is the neurotransmitter at the NMJ, so toxins that block vesicle fusion (botulinum toxin) prevent Ach release so effectively paralyze the muscle. This is useful therapeutically for blepharospasm (spasm of the eyelid), strabismus, spasmodic torticollis, drooling associated with cerebral palsy, and more recently, for cosmetic wrinkle reduction.
Glaucoma
Pilocarpine, a muscarinic agonist, is used to reduced intraocular pressure in glaucoma.
