CHRM4

CHRM4 Full Name

cholinergic receptor, muscarinic 4

CHRM4 Introduction

The muscarinic cholinergic receptors belong to a larger family of G protein coupled receptors. The functional diversity of these receptors is determined by the binding of acetylcholine, including adenylate cyclase inhibition, phosphoinositol denaturation, and potassium channel mediated cellular responses. The muscarinic receptors affect many functions of acetylcholine in the central and peripheral nervous systems. The muscarinic acetylcholine receptor M4 is a member of the G protein coupled receptor (GPCR) family and responds to the neurotransmitter acetylcholine. It is classified as a class II muscarinic receptor subgroup (along with M2), characterized by primarily coupling with inhibitory Gi/o proteins. The M4 receptor serves as a key self receptor and heterogeneous receptor in specific brain circuits, with its main function being to inhibit neuronal excitability and neurotransmitter release. It is mainly expressed in the central nervous system (CNS) and plays a non redundant role in regulating motor control, reward pathways, and cognitive processes. Its selective positioning and function make it a striking target for new therapies in neurology and psychiatry.

Figure. Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia.(Source: .Jones CK, et al, 2021)

Function
M4 muscarine receptors have been found to be regulatory factors for the differentiation of erythroid progenitor cells. Inhibition of M4 muscarinic receptors has therapeutic benefits for myelodysplastic syndrome and anemia. The specific localization of M4 receptors determines their core role in brain function. They act as inhibitory self receptors for acetylcholine. The activation of M4 receptors inhibits the release of acetylcholine in the striatum. The function of M2 subtype acetylcholine receptors is similar to that of inhibitory self receptors for acetylcholine release, although they mainly function in the hippocampus and cerebral cortex. The M4 receptor regulates dopamine release in the midbrain limbic pathway, regulates cholinergic activity in the cortex and hippocampus, and affects various aspects of reward processing, motivation, learning, and memory. Preclinical models have shown that enhancing M4 activity can produce antipsychotic like and cognitive promoting effects.

Expression and Positioning
M4 receptors are highly enriched in the central nervous system and have unique regional patterns that define their functional roles.
The striatum is a critical area of the brain for motor and reward processing, with the highest density. In the striatum, it is mainly located on the axis of dendritic spines and middle spine neurons (MSNs), which are the main output neurons. It is particularly associated with a subset of these neurons that form a direct pathway (expressing dopamine D1 receptors), where it exerts inhibitory control. There is also significant expression in the cerebral cortex, hippocampus, and amygdala, indicating its association with cognitive and emotional functions. Lower levels of M4 receptors have been detected in some peripheral tissues outside the central nervous system, such as the lungs and pancreas, although their physiological roles there are still unclear.

Alternate Names for CHRM4

CHRM4; cholinergic receptor, muscarinic 4; HM4; M4R; muscarinic acetylcholine receptor M4; acetylcholine receptor, muscarinic 4;

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• 1.Jones CK, Byun N, Bubser M. Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia. Neuropsychopharmacology. 2012, 37(1):16-42.