| CHRM2 | |
|---|---|
| Protein Name | Muscarinic Acetylcholine Receptor M2 |
| Gene | CHRM2 |
| UniProt ID | P08172 |
| Protein Family | GPCR, Class A, Muscarinic |
| Molecular Weight | 66.7 kDa |
| Expression | Heart, brain, smooth muscle |
| Signal Transduction | Gi/o-coupled, ↓cAMP |
CHRM2 (Muscarinic Acetylcholine Receptor M2) is a Gi/o-protein-coupled receptor that mediates inhibitory cholinergic signaling in the heart, smooth muscle, and central nervous system. In the brain, M2 receptors play crucial roles in modulating neurotransmitter release, regulating cognitive processes, and maintaining neuronal network stability. CHRM2 has been implicated in Alzheimer's disease, Parkinson's disease, and various neuropsychiatric disorders [1].
CHRM2 is a seven-transmembrane domain GPCR consisting of 460 amino acids. The receptor contains:
The binding of acetylcholine or other muscarinic agonists induces conformational changes that activate downstream signaling cascades.
CHRM2 preferentially couples to Gi/o proteins, leading to:
This Gi/o coupling distinguishes M2 from M1/M3/M5 receptors, which couple to Gq proteins and activate phospholipase C.
In the central nervous system, CHRM2 is highly expressed in:
CHRM2 regulates several critical brain functions:
M2 receptors function as autoreceptors on cholinergic neurons, limiting acetylcholine release during high activity. They also modulate release of:
CHRM2 is implicated in:
In peripheral tissues, CHRM2 mediates:
CHRM2 plays a complex role in Alzheimer's disease:
The cholinergic hypothesis of AD posits that loss of basal forebrain cholinergic neurons contributes to cognitive decline. CHRM2 autoreceptors are strategically positioned to modulate this system:
Evidence suggests bidirectional interactions between amyloid-beta and muscarinic receptors:
In Parkinson's disease, CHRM2 influences:
Genome-wide association studies (GWAS) have identified CHRM2 polymorphisms associated with:
Muscarinic agonists (e.g., xanomeline, talsaclidine) have been investigated for AD treatment:
M2 antagonists are being explored for:
Positive allosteric modulators (PAMs) offer potential advantages:
CHRM2 is a critical Gi/o-coupled muscarinic receptor that regulates cholinergic signaling throughout the brain. Its role in modulating neurotransmitter release, cognitive processes, and neuronal survival makes it a key player in neurodegenerative diseases. While direct muscarinic agonists have shown promise, their utility is limited by peripheral side effects. Allosteric modulation and subtype-selective targeting represent promising therapeutic strategies for AD and PD.