Muscarinic acetylcholine receptor
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Muscarinic receptors are those membrane bound acetylcholine receptors that are more sensitive to muscarine than to nicotine. Those for which the contrary is true are known as nicotinic acetylcholine receptors. Muscarine and nicotine are both alkaloids. Many drugs and other substances (for example atropine and scopolamine) act as agonists or antagonists of only muscarinic or only nicotinic receptors, making this distinction useful.
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Acetylcholine receptors, of which muscarinic receptors are a subdivision, are widely distributed in both the central nervous system and the autonomic nervous system. The autonomic nervous system is anatomically distinct from the somatic nervous system. The autonomic nervous system controls various involuntary actions, such as heart rate, pupil dilation, sweating, salivation, urination and defecation, digestion, and so on. Though these actions are known as 'involuntary', that is not to say that the conscious mind is unaware of these actions, or unable to influence them. It is the autonomic nervous system about which the most is known concerning muscarinic receptors.
The autonomic nervous system is divided into two parts, the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is responsible for sweating, bronchodilation, increased heart-rate and blood pressure, decreased digestion, and so on, (often summarised as flight or fight) whereas the parasympathetic nervous system is responsible for salivation, decreased heart-rate, the accommodation of the eye for near-work, digestion, and so on (often summarised as rest and digest). The distribution of muscarinic receptors crucially differs between the sympathetic and the parasympathetic nervous system, a full discussion of which follows.
A further necessary distinction to make in a description of muscarinic receptors is that, in contrast to the voluntary nervous system -- which consists of a single nerve cell extending from the central nervous system to the synapse between that nerve and the innervated organ -- the autonomic nervous system consists of two nerve cells. The junction between these cells is a ganglion, usually located in or near the target organ. The nerve extending from the central nervous system to the ganglion is known as the preganglionic neurone. The nerve extending from the ganglion to the innervated tissue is known as the postganglionic neurone.
Physiology
Acetylcholine (ACh) is a neurotransmitter extensively found in brain and autonomic nervous system.
ACh is always used as the transmitter within the autonomic ganglion. Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarisation (Fast EPSP) of that neurone. As a consequence of this, nicotinic receptors are often cited as the receptor on the postganglionic neurone at the ganglion. However, the subsequent hyperpolarisation (IPSP) and slow depolarisation (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 autonomic nervous system. Here acetylcholine is again used as a neurotransmitter, and muscarinic receptors form the principal receptors on the innervated tissue. In addition, muscinaric acetylcholine receptors pre-synaptically on the post-ganglionic neuron bind to the released acetylcholine and regulate the response of the postganglionic neurone.
By contrast, this junction in the sympathetic division does not tend to use acetylcholine as a neurotransmitter, and therefore neither muscarinic nor nicotinic receptors are involved. A very few parts of the sympathetic system (sweating, for example), do use acetylcholine as a neurotransmitter at this position. 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 adrenaline and noradrenaline 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 distributed throughout the central nervous system, in post-synaptic and pre-synaptic postions. There is also some evidence for postsynaptic receptors on sympathetic neurons allowing the parasympathetic nervous system to inhibit sympathetic effects.
In summary then, muscarinic receptors can be found:
- Between the postganglionic neurone and the innervated tissue throughout the parasympathetic nervous system.
- Presynaptically within the postganglionic neurone to regulate acetylcholine release in the parasympathetic nervous system.
- Between the postganglionic neurone and the innervated tissue in a very few parts of the sympathetic nervous system.
- Within the ganglions of the whole autonomic nervous system (sympathetic and parasympathetic), acting as recovery receptors after the primary stimulation of the postganglionic neurone by action on nicotinic receptors by ACh from the preganglionic neurone.
- In various parts of the higher central nervous system, which are currently poorly characterised, but have a role in cognition and memory, and degenerate in Alzheimer's disease.
The Form of Muscarinic Receptors
Muscarinic receptors belong to a class of receptors which use G proteins as their signalling mechanism. There are known to be a large number of G protein receptors for neuroreceptors, hormones, and other substances. G proteins are also present in taste, and odour detecting cells, in the retina, and in many other systems.
In such receptors, the signalling molecule (the ligand) binds to a receptor which has seven trans-membrane regions, in our case the ligand is ACh. This receptor is bound to intra-cellular proteins, known as G-proteins, which begin the information cascade within the cell.
By contrast nicotinic receptors use an ion-gated mechanism for signalling. Sufficient ligands cause an ion-channel to open, filling (or evacuating) a cell of a particular ion.
Variety of Receptor Forms
By the use of selective radioactively-labelled agonist and antagonist substances, four sybtypes of muscarinic receptors have been determined, named M1-M4 (using an upper case M). For example, the drug pirenzepine is a muscinaric 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 has proceeded in numerical order: therefore, sources exist which only recognise the M1/M2 distinction, more recent studies tend to recognise M3, and the most recent M4.
Meanwhile, geneticists and molecular biologists have characterised five genes which appear to encode muscinaric receptors, named m1-m5 (lower case m). The first four code for pharmacologic types M1-M4. The fifth, m5, corresponds to a subtype of receptor which has not been detected pharmacologically. m1 and m2 were determined based upon partial sequencing of M1 and M2 receptor proteins, the others were found by searching for homology, using bioinformatic techniques.
G-proteins contain an alpha-subunit which 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, G_s, G_i, G_q and G_12[5]. 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 succeptibility to cholera toxin (CTX) and pertussis toxin (PTX, whooping cough). G_s and some subtypes of G_i (G_alpha_t and G_alpha_g) are succeptible to CTX. Only G_i is succeptible to PTX, with the exception of one subtype of G_i (G_alpha_z) which is immune. Also, only when bound with an agonist, those G proteins normally sensitive to PTX also become succeptible to CTX[4].
The various G-protein subunits act differently upon secondary messangers, 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.
Receptor Subtype m1
This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve[1], is common in secretory glands (exocrine glands)[2,3], and in the cns [2,3]. It is predominantly found bound to G proteins of class G_q[6] which use upregulation of phospholipase C and therefore Inositol Triphosphate and intracellular calcium as a signalling pathway. A receptor so bound would not be succeptible to CTX or PTX. However, G_i[3] (causing a downstream decrease in cAMP) and G_s[8] (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be succeptible to PTX and CTX respectively.
m2
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M2: These receptors are found in cardiac tissue and cause a slowing of sinoatrial depolarization and a decrease in conduction velocity.
The M2 muscarinic receptors are located in the heart, they act to bring the heart back to normal after the actions of the Sympathetic nervous system. They slow down the heart rate, reduce contractile forces of the atrial cardiac muscle, and reduce conduction velocity of the Atrioventricular node (AV node). Note, they have no effect on the contractile forces of the ventricular muscle.
m3
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M3: These receptors are found on smooth muscles and in glands. M3 receptors generally cause smooth muscle contraction and increased glandular secretions.
m4
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m5
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References
- The Pharmacology and Chemistry of Muscarinic Receptor Agonists and Antagonists: Drugs for Alzheimer's Disease?. Kenneth J Broadley, David R Kelly. Chemistry Preprint Server: medichem/0009001
- PDQ Pharmacology. Gordon E Johnson. ISBN 1550091093. BC Decker.
- Cholinergic Transduction. Elliot Richelson. The Fourth Generation of Progress. The American College of Neuropsychopharmacology.
- Muscarinic Receptor Regulation of PTX-sensitive G-proteins. Mark L Dell'Acqua, Reed C Carrol, Ernest G Peralta. Journal of Biomedical Chemistry.
- G protein diversity in signal transduction. Science 1991; 252:802-808. Simon MI, Strathmann M, Gautam N.
- G protein diversity and complexity in G-protein Signaling. RA Fisher. University of Iowa, Lecture Notes, 2004.
- A novel mechanism for coupling of M4-muscarinic acetylcholine-receptors to calmodulin-sensitive adenylyl cyclases - crossover from G protein-coupled inhibition to stimulation. AH Dittman, JP Weber, TR Hinds, et al.
- Muscarinic m1 receptor-stimulated adenylate cyclase activity in Chinese hamster ovary cells is mediated by Gs alpha and is not a consequence of phosphoinositidase C activation.. Burford NT, Nahorski SR.
- University of Sydney lecture notes on the M2 receptors.