The muscarinic acetylcholine receptor M₄, also known as the cholinergic receptor, muscarinic 4 (CHRM4), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that, in humans, is encoded by the ''CHRM4''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

Function

M₄

muscarinic 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, lab ...

receptors are coupled to G_i/o heterotrimeric proteins. They function as inhibitory

autoreceptors An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the aut ...

for acetylcholine. Activation of M₄ receptors inhibits

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

release in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

. The M₂ subtype of acetylcholine receptor functions similarly as an inhibitory autoreceptor to acetylcholine release, albeit functioning actively primarily in the

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

and

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. It is the largest site of Neuron, neural integration in the central nervous system, and plays ...

Muscarinic acetylcholine receptors 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-recept ...

possess a regulatory effect on

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron ...

. Activation of M₄ receptors in the

inhibit D₁-induced locomotor stimulation in

mice A mouse (: mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

. M₄ receptor-deficient mice exhibit increased locomotor simulation in response to D₁ agonists,

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

and

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

. Neurotransmission in the striatum influences extrapyramidal

motor control Motor control is the regulation of movements in organisms that possess a nervous system. Motor control includes conscious voluntary movements, subconscious muscle memory and involuntary reflexes, as well as instinctual taxes. To control ...

, thus alterations in M₄ activity may contribute to conditions such as

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. The M₄ muscarinic receptor has been found to be a regulator of erythroid

progenitor cell A progenitor cell is a biological cell that can differentiate into a specific cell type. Stem cells and progenitor cells have this ability in common. However, stem cells are less specified than progenitor cells. Progenitor cells can only diffe ...

differentiation. Inhibition of the M₄ muscarinic receptor provides therapeutic benefits in

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...

and

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

Ligands

Agonists

Acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

Carbachol Carbachol, also known as carbamylcholine and sold under the brand name Miostat among others, is a cholinomimetic drug that binds and activates acetylcholine receptors. Thus it is classified as a cholinergic agonist. It is primarily used for v ...

* CMI-936 *

NBI-1117568 NBI-1117568 (former developmental code name HTL-0016878) is an investigational antipsychotic drug for schizophrenia that was out-licensed Nexera Pharma in to Neurocrine Biosciences, a United States-based pharmaceutical company. It is administer ...

(HTL-0016878) *

ML-007 ML-007 is a selective muscarinic acetylcholine M1 and M4 receptor agonist which is under development for the treatment of schizophrenia, psychotic disorders, and dyskinesias. It is being developed in combination with a peripherally selectiv ...

Oxotremorine Oxotremorine is a drug that acts as a selective muscarinic acetylcholine receptor agonist. Oxotremorine produces ataxia, tremor and spasticity, similar to those symptoms seen in Parkinsonism, and has thus become a research tool in experimental s ...

Xanomeline Xanomeline (developmental code name LY-246,708) is a small molecule muscarinic acetylcholine receptor agonist that was synthesized in a collaboration between Eli Lilly and Novo Nordisk as an investigational therapeutic being studied for the tre ...

Positive allosteric modulators

Emraclidine Emraclidine (developmental code names CVL-231, PF-06852231) is an investigational antipsychotic for the treatment of both schizophrenia and Alzheimer's disease psychosis developed by Cerevel Therapeutics. On November 11, 2024, AbbVie announced ...

(CVL-231, PF-06852231) * LY-2033298 * NS-136 * SUVN-L3307032 * VU-0152100 (ML-108) * VU-0152099

Antagonists

AFDX-384 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 b ...

(mixed M2/M4 antagonist, N- -[2-[(Dipropylamino)methyl1-piperidinyl">-[(Dipropylamino)methyl.html" ;"title="-[2-[(Dipropylamino)methyl">-[2-[(Dipropylamino)methyl1-piperidinylthyl]-5,6-dihydro-6-oxo-11H-pyrido[2,3-b][1,4]benzodiazepine-11-carboxamide, CAS# 118290-27-0) * Dicycloverine * Diphenhydramine * Himbacine * Mamba toxin 3 * NBI-1076968 * PD-102,807 (3,6a,11,14-Tetrahydro-9-methoxy-2-methyl-(12H)-isoquino ,2-byrrolo ,2-f1,3]benzoxazine-1-carboxylic acid ethyl ester, CAS# 23062-91-1) * PD-0298029 *

Tropicamide Tropicamide, sold under the brand name Mydriacyl among others, is a medication used to dilate the pupil and help with the examination of the eye. Specifically it is used to help examine the back of the eye. It is applied as eye drops. Effect ...

- moderate selectivity over other muscarinic subtypes (2-5x approx) * VU6028418

References

External links

* {{DEFAULTSORT:Muscarinic Acetylcholine Receptor M4 G protein-coupled receptors Human proteins Muscarinic acetylcholine receptors