CHRM5

CHRM5 Full Name

cholinergic receptor, muscarinic 5

CHRM5 Introduction

The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) was the most recent mAChR to be cloned and has since emerged as a potential therapeutic target for a number of indications. The muscarinic acetylcholine receptor M5 is the least studied and recently discovered member of the muscarinic acetylcholine receptor family (M1-M5). Like M1 and M3, it is classified as a class I receptor and primarily couples with Gq/11 protein. Among all subtypes of muscarinic acid, its expression in vivo is the most restricted, only found in a few specific locations. In the central nervous system (CNS), it mainly exists in the substantia nigra and ventral tegmental area, where it crucially regulates dopaminergic signaling. Due to its involvement in pathways related to reward, addiction, and potential central inflammation, the M5 receptor is an emerging target for research on substance use disorders and neurodegenerative diseases.

Figure. Structure of CHRM5.

Signal Mechanism and Cellular Function
After acetylcholine activation, the M5 receptor binds to the Gq/11 signaling pathway. This leads to the activation of phospholipase C - β (PLC β), which catalyzes the hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP) into two key second messengers: inositol triphosphate (IP ∝) and diacylglycerol (DAG). IP ∝ DAG activates protein kinase C (PKC). In dopaminergic neurons, this signal cascade leads to membrane depolarization and increased neuronal excitability, ultimately promoting the discharge and subsequent release of dopamine in projection areas such as the striatum and nucleus accumbens. This makes the M5 receptor a direct positive regulator of dopamine transmission.

Clinical Significance
The direct connection between M5 receptor and dopaminergic tone makes it a striking target for several neurological and psychiatric disorders. Its most prominent therapeutic potential lies in the areas of substance use disorders and addiction. In theory, M5 receptor antagonists can inhibit drug-induced dopamine surges in the reward circuit, thereby reducing craving and relapse behavior without affecting the basal dopamine signaling required for normal motivation. Understanding the role of M5 receptors on remaining neurons in Parkinson's disease with dopaminergic neuron degeneration can provide information for strategies to regulate circuit activity. Furthermore, due to its presence on specific immune cells (microglia) in the brain under inflammatory conditions, the M5 receptor is hypothesized to play a role in neuroinflammation, potentially linking it to diseases such as Alzheimer's.

Alternate Names for CHRM5

CHRM5; cholinergic receptor, muscarinic 5; HM5; muscarinic acetylcholine receptor M5; acetylcholine receptor, muscarinic 5;