The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene. [5] [6]
The muscarinic acetylcholine receptor M4, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a protein that, in humans, is encoded by the CHRM4 gene. [5] [6]
M4 muscarinic receptors are coupled to Gi/o heterotrimeric proteins. [7]
They function as inhibitory autoreceptors for acetylcholine. Activation of M4 receptors inhibits acetylcholine release in the striatum. The M2 subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the hippocampus and cerebral cortex.
Muscarinic acetylcholine receptors possess a regulatory effect on dopaminergic neurotransmission. Activation of M4 receptors in the striatum inhibit D1-induced locomotor stimulation in mice. M4 receptor-deficient mice exhibit increased locomotor simulation in response to D1 agonists, amphetamine and cocaine. [8] [9] [10] Neurotransmission in the striatum influences extrapyramidal motor control, thus alterations in M4 activity may contribute to conditions such as Parkinson's disease. [11] [12] [13]
The M4 muscarinic receptor has been found to be a regulator of erythroid progenitor cell differentiation. Inhibition of the M4 muscarinic receptor provides therapeutic benefits in myelodysplastic syndrome and anemia. [14] [15] [16]
Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
An acetylcholine receptor or a cholinergic receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system, and (2) they are the receptors found on skeletal muscle that receive acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways. In insects, the cholinergic system is limited to the central nervous system.
Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers. They are mainly found in the parasympathetic nervous system, but also have a role in the sympathetic nervous system in the control of sweat glands.
A muscarinic acetylcholine receptor agonist, also simply known as a muscarinic agonist or as a muscarinic agent, is an agent that activates the activity of the muscarinic acetylcholine receptor. The muscarinic receptor has different subtypes, labelled M1-M5, allowing for further differentiation.
A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarinic receptors are proteins involved in the transmission of signals through certain parts of the nervous system, and muscarinic receptor antagonists work to prevent this transmission from occurring. Notably, muscarinic antagonists reduce the activation of the parasympathetic nervous system. The normal function of the parasympathetic system is often summarised as "rest-and-digest", and includes slowing of the heart, an increased rate of digestion, narrowing of the airways, promotion of urination, and sexual arousal. Muscarinic antagonists counter this parasympathetic "rest-and-digest" response, and also work elsewhere in both the central and peripheral nervous systems.
The human muscarinic acetylcholine receptor M5, encoded by the CHRM5 gene, is a member of the G protein-coupled receptor superfamily of integral membrane proteins. It is coupled to Gq protein. Binding of the endogenous ligand acetylcholine to the M5 receptor triggers a number of cellular responses such as adenylate cyclase inhibition, phosphoinositide degradation, and potassium channel modulation. Muscarinic receptors mediate many of the effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor have not been fully explored; however, stimulation of this receptor is known to effectively decrease cyclic AMP levels and downregulate the activity of protein kinase A (PKA).
The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor that in humans is encoded by the CHRM1 gene. It is localized to 11q13.
The muscarinic acetylcholine receptor M2, also known as the cholinergic receptor, muscarinic 2, is a muscarinic acetylcholine receptor that in humans is encoded by the CHRM2 gene. Multiple alternatively spliced transcript variants have been described for this gene. It is Gi-coupled, reducing intracellular levels of cAMP.
The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.
Neuronal acetylcholine receptor subunit alpha-4, also known as nAChRα4, is a protein that in humans is encoded by the CHRNA4 gene. The protein encoded by this gene is a subunit of certain nicotinic acetylcholine receptors (nAChR). Alpha4-containing nAChRs appear to play a crucial role in the addictive response to nicotine.
Neuronal acetylcholine receptor subunit beta-3 is a protein that in humans is encoded by the CHRNB3 gene. This gene has been identified as a candidate for predisposition to tobacco dependence.
Xanomeline is a small molecule muscarinic acetylcholine receptor agonist that was first synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the treatment of central nervous system (CNS) disorders.
PD-102,807 is a drug which acts as a selective antagonist for the muscarinic acetylcholine receptor M4. It is used in scientific research for studying the effects of the different muscarinic receptor subtypes in the body and brain.
VU-0238429 is a drug which acts as a selective positive allosteric modulator for the muscarinic acetylcholine receptor M5. It was the first selective ligand developed for the M5 subtype, and is structurally derived from older M1-selective positive allosteric modulators such as VU-0119498. Replacing the O-methyl- by a phenyl group further improves the receptor subtype selectivity.
AFDX-384 (BIBN-161) is a drug which acts as a selective antagonist of the muscarinic acetylcholine receptors, with selectivity for the M2 and M4 subtypes. It is used mainly for mapping the distribution of M2 and M4 muscarinic receptors in the brain, and studying their involvement in the development and treatment of dementia and schizophrenia.
Arthur Christopoulos is an Australian Professor of Analytical Pharmacology at Monash University. He was a Councillor of the International Union of Basic and Clinical Pharmacology from 2018 to 2022. In 2019 he was appointed Dean of Monash University's Faculty of Pharmacy and Pharmaceutical Sciences and from 2021 to 2023 he served as the inaugural Director of Monash University's Neuromedicines Discovery Centre. He was elected a Fellow of the Australian Academy of Science in 2021.
Emraclidine is an investigational antipsychotic for the treatment of both schizophrenia and Alzheimer's disease psychosis developed by Cerevel Therapeutics. As of August 2024, it is in phase 2 clinical trials.
VU-0152100 is a positive modulator of the M4 receptor, one of the muscarinic acetylcholine receptors.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.