Muscarinic acetylcholine receptor
They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers.
Many drugs and other substances (for example pilocarpine and scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists.
The chromaffin cells of the adrenal medulla act as "modified neurons", releasing adrenaline and noradrenaline into the bloodstream as hormones instead of as neurotransmitters.
Another role for these receptors is at the junction of the innervated tissues and the postganglionic neurons in the parasympathetic division of the autonomic nervous system.
The sympathetic nervous system also has some preganglionic nerves terminating at the chromaffin cells in the adrenal medulla, which secrete epinephrine and norepinephrine into the bloodstream.
Muscarinic acetylcholine receptors are also present and distributed throughout the local nervous system, in post-synaptic and pre-synaptic positions.
[5] By contrast, nicotinic receptors form pentameric complexes and use a ligand-gated ion channel mechanism for signaling.
By the use of selective radioactively labeled agonist and antagonist substances, five subtypes of muscarinic receptors have been determined, named M1–M5 (using an upper case M and subscript number).
For example, the drug pirenzepine is a muscarinic antagonist (decreases the effect of ACh), which is much more potent at M1 receptors than it is at other subtypes.
[citation needed] Meanwhile, geneticists and molecular biologists have characterised five genes that appear to encode muscarinic receptors, named m1-m5 (lowercase m; no subscript number).
[8] The various G-protein subunits act differently upon secondary messengers, upregulating Phospholipases, downregulating cAMP, and so on.
The muscarinic acetylcholine receptor subtype sectivities of a large number of antimuscarinic drugs have been reviewed.
[27] This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve,[28] is common in exocrine glands and in the CNS.
[29][30] It is predominantly found bound to G proteins of class Gq,[31] which use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.
Because the M3 receptor is Gq-coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed during bronchoconstriction and bladder voiding.
[36] In early clinical trials of moderate to high severity patients without treatment resistant history, it has demonstrated efficacy about equivalent to that of other anti-psychotics (20-point improvement in PANSS vs 10-point placebo improvement), with a notably different side effect profile (very low rates of metabolic effects, hypotension, weight changes, or EPS) with moderately reported rates of nausea and constipation.
No trials have been published to date regarding use in combination with other antipsychotics, use in treatment resistant patients, or head-to-head comparisons with other medications.
