Muscarinic acetylcholine receptors

Muscarinic acetylcholine receptors are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells.


They act as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.



Acetylcholine is the natural agonist of muscarinic and nicotinic receptors.



Atropine  is an acetylcholine muscarinic antagonist.



Muscarinic receptors are more sensitive to muscarine than to nicotine.



Muscarinic receptor counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. 



Pilocarpine and scopolamine manipulate these two distinct receptors by acting as selective agonists or antagonists.



Acetylcholine is a neurotransmitter located in the brain, neuromuscular junctions and the autonomic ganglia. 



ACh is the neurotransmitter within the autonomic ganglion. 



Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarization of that neuron. 



As a consequence of this, nicotinic receptors are often cited as the receptor on the postganglionic neurons at the ganglion. 



The  subsequent hyperpolarization and slow depolarization that represent the recovery of the postganglionic neuron from stimulation are actually mediated by muscarinic receptors, types M2 and M1 respectively.



Peripheral autonomic fibers of the sympathetic and parasympathetic fibers are categorized as either preganglionic or postganglionic fibers.



Peripheral autonomic fibers are further generalized as either adrenergic fibers, releasing noradrenaline, or cholinergic fibers, both releasing acetylcholine and expressing acetylcholine receptors. 



Preganglionic sympathetic fibers and preganglionic parasympathetic fibers are cholinergic. 



Most postganglionic sympathetic fibers are adrenergic, as their neurotransmitter is norepinephrine: except postganglionic sympathetic fibers to the sweat glands, piloerectile muscles of the body hairs, and the skeletal muscle arterioles do not use adrenaline/noradrenaline.



The adrenal medulla is considered a sympathetic ganglion and, like other sympathetic ganglia, is supplied by cholinergic preganglionic sympathetic fibers.



Acetylcholine is the neurotransmitter utilized at this sympathetic ganglion synapse. 



The chromaffin cells of the adrenal medulla release adrenaline and noradrenaline into the bloodstream as hormones instead of as neurotransmitters. 



The other postganglionic fibers of the peripheral autonomic system belong to the parasympathetic division; all are cholinergic fibers, and use acetylcholine as the neurotransmitter.



In the parasympathetic division of the autonomic nervous system,  acetylcholine is used as a neurotransmitter, and muscarinic receptors form the principal receptors on the innervated tissue.



Very few parts of the sympathetic system use cholinergic receptors. 



Sweat glands the receptors are of the muscarinic type. 



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. 



In the adrenal medulla, acetylcholine is used as a neurotransmitter, and the receptor is of the nicotinic type.



The somatic nervous system uses a nicotinic receptor to acetylcholine at the neuromuscular junction.



Muscarinic acetylcholine receptors are also present throughout the local nervous system, in post-synaptic and pre-synaptic positions. 



Muscarinic acetylcholine receptors also appear on the pre-synaptic membrane of somatic neurons in the neuro-muscular junction, where they are involved in the regulation of acetylcholine release.



Muscarinic acetylcholine receptors


use G proteins as their signaling mechanism. 



Nicotinic receptors use a ligand-gated ion channel mechanism for signaling. 



Five subtypes of muscarinic receptors have been determined, named M1-M5.



M1,M3,M5 receptors are coupled with Gq proteins.



M2 and M4 receptors are coupled with Gi/o proteins.



G proteins contain an alpha-subunit that is critical to the functioning of receptors. 



There are four broad classes of form of G-protein: Gs, Gi, Gq, and G12/13.



The various G-protein subunits act differently upon secondary messengers, upregulating  phospholipases, or down regulating cAMP.



Muscarinic acetylcholine receptor M1


 mediates slow excitable


postsynaptic potential  at the ganglion in the postganglionic nerve and is common in exocrine glands and in the CNS.



The M2 muscarinic receptors are located in the heart.



M2 muscarinic receptors act to slow the heart rate down below the normal baseline sinus rhythm, by slowing the speed of depolarization. 



In the resting state vagal activity dominates over sympathetic activity. 



Inhibition of M2 receptors by a drug like atropine, will cause a raise in heart rate. 



Such inhibitors moderately reduce contractile forces of the atrial cardiac muscle, and reduces conduction velocity of the atrioventricular node (AV node, and slightly decreases the contractile forces of the ventricular muscle.



M2 muscarinic receptors act via a Gi type receptor, decreasing cAMP in the cell, inhibition of voltage-gated Ca2+ channels, and increasing efflux of K+, in general, leading to inhibitory-type effects.



The M3 muscarinic receptors are located


in the smooth muscles of the blood vessels, as well as in the lungs. 



The M3 receptor is Gq-coupled and mediates: increases in intracellular calcium, contraction of smooth muscle, such as that observed during bronchoconstriction and bladder voiding.



The activation of M3 on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation.



These findings explain the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. 



M3 mediates vasconstriction in pathologies when the vascular endothelium is disrupted.



M3 receptors are also located in many glands, which help to stimulate secretions:  salivary and other glands of the body.



M3 receptors are G proteins of class Gq that upregulate intracellular calcium as a signaling pathway.



M4 receptors are found in the CNS, 


work via Gi receptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects. 



Possible bronchospasm may result if stimulated by muscarinic agonists



Location of M5 receptors is not well understood.



M5 receptors are coupled with G proteins of class Gq that upregulate phospholipase C, inositol trisphosphate and intracellular calcium as a signaling pathway.



Ligands targeting the muscarinic acetylcholine receptors in clinical use include: non-selective antagonists for the treatment of Parkinson’s disease, atropine, scopolamine, and ipratropium, used in the treatment of COPD).





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