Muscarinic acetylcholine receptor

Source: Wikipedia, the free encyclopedia.
Acetylcholine - the natural agonist of muscarinic and nicotinic receptors.
Muscarine - an agonist used to distinguish between these two classes of receptors. Not normally found in the body.
Atropine - an antagonist.

Muscarinic acetylcholine receptors, or mAChRs, are

postganglionic fibers in the parasympathetic nervous system
.

Muscarinic receptors are so named because they are more sensitive to

scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists.[3]

Function

autonomic ganglia
. Muscarinic receptors are used in the following roles:

Recovery receptors

The structure of Muscarinic acetylcholine receptor M2.

IPSP) and slow depolarization (Slow EPSP) that represent the recovery of the postganglionic neuron from stimulation are actually mediated by muscarinic receptors, types M2 and M1 respectively (discussed below).[citation needed
]

Peripheral autonomic fibers (sympathetic and parasympathetic fibers) are categorized anatomically as either preganglionic or

postganglionic fibers
, then further generalized as either adrenergic fibers, releasing noradrenaline, or cholinergic fibers, both releasing acetylcholine and expressing acetylcholine receptors. Both preganglionic sympathetic fibers and preganglionic parasympathetic fibers are cholinergic. Most postganglionic sympathetic fibers are adrenergic: 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

chromaffin cells
of the adrenal medulla act as "modified neurons", releasing 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.

Postganglionic neurons

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. Here acetylcholine is again used as a neurotransmitter, and muscarinic receptors form the principal receptors on the innervated tissue.

Innervated tissue

Very few parts of the sympathetic system use cholinergic receptors. In sweat glands the receptors are of the muscarinic type. The sympathetic nervous system also has some preganglionic nerves terminating at the

epinephrine and norepinephrine into the bloodstream. Some[who?
] believe that chromaffin cells are modified postganglionic CNS fibers. In the adrenal medulla, acetylcholine is used as a neurotransmitter, and the receptor is of the nicotinic type.

The

nicotinic
receptor to acetylcholine at the neuromuscular junction.

Higher central nervous system

Muscarinic acetylcholine receptors are also present and distributed throughout the local nervous system, in post-synaptic and pre-synaptic positions. There is also some evidence for

postsynaptic
receptors on sympathetic neurons allowing the parasympathetic nervous system to inhibit sympathetic effects.

Presynaptic membrane of the neuromuscular junction

It is known that 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.

Form of muscarinic receptors

Muscarinic acetylcholine receptors belong to a class of

seven transmembrane regions; in this case, the ligand is ACh. This receptor is bound to intracellular proteins, known as G proteins, which begin the information cascade within the cell.[4]

By contrast, nicotinic receptors form pentameric complexes and use a ligand-gated ion channel mechanism for signaling. In this case, binding of the ligands with the receptor causes an ion channel to open, permitting either one or more specific types of ions (e.g., K+, Na+, Ca2+) to diffuse into or out of the cell.

Receptor isoforms

Classification

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).[5] M1, M3, M5 receptors are coupled with Gq proteins, while M2 and M4 receptors are coupled with Gi/o proteins.[4] There are other classification systems. 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. The acceptance of the various subtypes proceeded in numerical order, therefore, earlier sources may recognize only M1 and M2 subtypes,[citation needed] while later studies recognize M3, M4,[1] and most recently M5 subtypes.[citation needed]

Genetic differences

Meanwhile,

bioinformatic
techniques.

Difference in G proteins

G proteins contain an alpha-subunit that is critical to the functioning of receptors. These subunits can take a number of forms. There are four broad classes of form of G-protein: Gs, Gi, Gq, and G12/13.[6] Muscarinic receptors vary in the G protein to which they are bound, with some correlation according to receptor type. G proteins are also classified according to their susceptibility to cholera toxin (CTX) and pertussis toxin (PTX, whooping cough). Gs and some subtypes of Gi (Gαt and Gαg) are susceptible to CTX. Only Gi is susceptible to PTX, with the exception of one subtype of Gi (Gαz) which is immune. Also, only when bound with an agonist, those G proteins normally sensitive to PTX also become susceptible to CTX.[7]

The various G-protein subunits act differently upon secondary messengers, upregulating Phospholipases, downregulating cAMP, and so on.

Because of the strong correlations to muscarinic receptor type, CTX and PTX are useful experimental tools in investigating these receptors.

Comparison of types
Type Gene Function PTX CTX Effectors Agonists[8] Antagonists[8]
M1 CHRM1 no
(yes)
no
(yes)
Gq
(Gi)
(Gs):
Slow EPSP.
K+ conductance[11][15]
M2 CHRM2 yes no Gi
K+ conductance[11]
Ca2+ conductance[11]


M3 CHRM3 no no Gq
M4 CHRM4 yes ? Gi
K+ conductance[11]
Ca2+ conductance[11]


M5
CHRM5
no ? Gq

M1 receptor

This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve[citation needed], is common in exocrine glands and in the CNS.[23][24]

It is predominantly found bound to G proteins of class Gq,[25] which use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, Gi (causing a downstream decrease in cAMP) and Gs (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX, respectively.

M2 receptor

The M2 muscarinic receptors are located in the heart and lungs. In the heart, they act to slow the

ventricular
muscle.

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

M3 receptor

The M3 muscarinic receptors are located at many places in the body. They are located in the smooth muscles of the blood vessels, as well as in the lungs. 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

parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle, M3 mediates vasoconstriction in diseases wherein the vascular endothelium is disrupted.[27]
The M3 receptors are also located in many glands, which help to stimulate secretion in, for example, the salivary glands, as well as other glands of the body.

Like the M1 muscarinic receptor, M3 receptors are G proteins of class Gq that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.[4]

M4 receptor

M4 receptors are found in the CNS.

M4 receptors 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

M5 receptor

Location of M5 receptors is not well known.

Like the M1 and M3 muscarinic receptor, M5 receptors are coupled with G proteins of class Gq that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.[citation needed]

Pharmacological application

COPD).[3][29]

See also

References

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  19. ^ a b Servent D, Blanchet G, Mourier G, Marquer C, Marcon E, Fruchart-Gaillard C (November 2011). "Muscarinic toxins". Toxicon. 58 (6–7): 455–63.
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    Human Metabolome Database, HMDB
    . 5.0.
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External links