Muscarinic receptors, or mAChRs, are acetylcholine receptors that form metabotropic ion channels in the plasma membranes of certain neurons. They are called "muscarinic" because they are more sensitive to muscarine than to nicotine. Those for which the contrary is true are known as nicotinic acetylcholine receptors (nAChRs). Many drugs and other substances (for example pilocarpine and scopolamine) act as selective agonists or antagonists of muscarinic or nicotinic receptors, making this distinction useful.
ACh is always used as the transmitter within the autonomic ganglion. Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarization (Fast EPSP) of that neuron. As a consequence of this, nicotinic receptors are often cited as the receptor on the postganglionic neurons at the ganglion. However, the subsequent hyperpolarization (IPSP) and slow depolarization (Slow EPSP) which represent the recovery of the postganglionic neuron from stimulation are actually mediated by muscarinic receptors, types M2 and M1 respectively (discussed later).
Another role for these receptors is at the junction of the innervated tissue and the postganglionic neuron in the parasympathetic division of the autonomous nervous system. Here acetylcholine is again used as a neurotransmitter, and muscarinic receptors form the principal receptors on the innervated tissue. In addition, muscarinic acetylcholine receptors pre-synaptically on the post-ganglionic neuron bind to the released acetylcholine and regulate the response of the postganglionic neuron.
By contrast, this junction in the sympathetic division does not tend to use acetylcholine as a neurotransmitter (instead, norepinephrine is used), and therefore neither muscarinic nor nicotinic receptors are involved, but rather adrenergic α1 and β1 receptors. A very few parts of the sympathetic system use cholinergic receptors (sweat glands being one of the few exceptions). In these cases, the receptors are of the muscarinic type. The sympathetic nervous system also has single nerves terminating at the chromaffin cells in the adrenal medulla, which secrete epinephrine and norepinephrine into the bloodstream. Acetylcholine is used as a neurotransmitter, and the receptor is of the nicotinic type. The somatic nervous system uses acetylcholine at the junction between its one peripheral nerve and the innervated tissue, also of the nicotinic type.
Muscarinic acetylcholine receptors are also present and distributed throughout the central 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.
It's now known they 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.
In such receptors, the signalling molecule (the ligand) binds to a receptor which has 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.
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.
| no |
| no |
| Gq |
↓ K+ conductance
|yes||no|| Gi |
↑ K+ conductance
↓ Ca2+ conductance
|yes||?|| Gi |
↑ K+ conductance
↓ Ca2+ conductance
It is predominantly found bound to G proteins of class Gq which use upregulation of phospholipase C and therefore inositol trisphosphate and intracellular calcium as a signalling 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 muscarinic receptors act via a Gi type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects.
The M3 receptors are also located in many glands which help to stimulate secretion in salivary glands and other glands of the body.
Like the M1 muscarinic receptor, M3 receptors are G proteins of class Gq which upregulate phospholipase C and therefore inositol trisphosphate and intracellular calcium as a signalling pathway.
Receptors work via Gi receptors to decrease cAMP in the cell and thus produce generally inhibitory effects.
Like the M1 and M3 muscarinic receptor, M5 receptors are coupled with G proteins of class Gq which upregulate phospholipase C and therefore inositol trisphosphate and intracellular calcium as a signalling pathway.
Wipo Publishes Patent of Vanderbilt University for "Substituted Benzylspiroindolin-2-One Analogs as Positive Allosteric Modulators of the Muscarinic Acetylcholine Receptor M1" (American Inventors)
May 18, 2013; GENEVA, May 18 -- Publication No. WO/2013/071201 was published on May 16.Title of the invention: "SUBSTITUTED...
Wipo Publishes Patent of Vanderbilt University for "Substituted 2-(4-Heterocyclylbenzyl)isoindolin-1-One Analogs as Positive Allosteric Modulators of the Muscarinic Acetylcholine Receptor M1" (American Inventors)
May 03, 2013; GENEVA, May 3 -- Publication No. WO/2013/063549 was published on May 2.Title of the invention: "SUBSTITUTED...