CHRM5 Gene

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CHRM5 Gene

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CHRM5 Gene — Muscarinic Acetylcholine Receptor 5

Introduction

CHRM5 (Cholinergic Receptor Muscarinic 5) encodes the M5 muscarinic acetylcholine receptor, also known as the M5 subtype. This receptor is a member of the muscarinic acetylcholine receptor family, which consists of five subtypes (M1-M5) that belong to the G protein-coupled receptor (GPCR) superfamily. The M5 receptor is the least studied of these subtypes, yet emerging research suggests it plays important roles in the central nervous system (CNS), particularly in regions affected by neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD)[@muscarinic].

The CHRM5 gene is located on chromosome 15q26 and encodes a 532-amino acid protein. Like other muscarinic receptors, M5 contains seven transmembrane domains connected by three extracellular and three intracellular loops, with an extracellular N-terminus and intracellular C-terminus. The receptor couples primarily to Gq/11 proteins, leading to activation of phospholipase C (PLC) and subsequent intracellular signaling cascades[@gqcoupled].

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CHRM5 Gene — Muscarinic Acetylcholine Receptor 5

Introduction

CHRM5 (Cholinergic Receptor Muscarinic 5) encodes the M5 muscarinic acetylcholine receptor, also known as the M5 subtype. This receptor is a member of the muscarinic acetylcholine receptor family, which consists of five subtypes (M1-M5) that belong to the G protein-coupled receptor (GPCR) superfamily. The M5 receptor is the least studied of these subtypes, yet emerging research suggests it plays important roles in the central nervous system (CNS), particularly in regions affected by neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD)[@muscarinic].

The CHRM5 gene is located on chromosome 15q26 and encodes a 532-amino acid protein. Like other muscarinic receptors, M5 contains seven transmembrane domains connected by three extracellular and three intracellular loops, with an extracellular N-terminus and intracellular C-terminus. The receptor couples primarily to Gq/11 proteins, leading to activation of phospholipase C (PLC) and subsequent intracellular signaling cascades[@gqcoupled].

| Property | Value |
|----------|-------|
| Gene Symbol | CHRM5 |
| Full Name | Cholinergic Receptor Muscarinic 5 |
| Chromosomal Location | 15q26 |
| NCBI Gene ID | 1129 |
| OMIM ID | 118491 |
| Ensembl ID | ENSG00000121966 |
| UniProt ID | P08912 |
| Encoded Protein | Muscarinic acetylcholine receptor M5 |
| Gene Type | Protein-coding |
| Protein Family | GPCR, Class A, Muscarinic receptors |
| Associated Diseases | Alzheimer's disease, Parkinson's disease, schizophrenia |

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Receptor Pharmacology and Signaling

G Protein Coupling

The M5 receptor is uniquely characterized by its selective coupling to Gq/11 proteins among the muscarinic receptor family. Unlike M1 and M3 receptors, which also couple to Gq/11, M5 appears to have more restricted G protein coupling. This specificity has important implications for its downstream signaling pathways and therapeutic targeting.

When activated by acetylcholine or muscarinic agonists, M5 triggers the following signaling cascade:

Mermaid diagram (expand to render)

Downstream Pathways

The M5 receptor activates multiple downstream signaling pathways:

Phospholipase C (PLC) pathway: Leads to generation of inositol trisphosphate (IP3) and diacylglycerol (DAG), causing calcium release and protein kinase C activation

MAPK pathway: Activation of ERK1/2 and p38 MAP kinases

PI3K/Akt pathway: Promotes cell survival and neuroprotection

cAMP pathway: Can modulate cAMP levels depending on cellular context

These pathways influence various neuronal functions including neurotransmitter release, synaptic plasticity, gene expression, and cell survival.

Ligand Pharmacology

The M5 receptor has traditionally been considered an "orphan" receptor due to the lack of highly selective ligands. However, several compounds have been developed:

Non-selective muscarinic agonists: Oxotremorine, pilocarpine, carbachol (activate all subtypes)
M5-preferring compounds: Several synthetic compounds show some selectivity for M5
Allosteric modulators: Positive and negative allosteric modulators (PAMs and NAMs) have been identified

The development of M5-selective ligands remains an active area of research due to the therapeutic potential of subtype-selective targeting.

Brain Distribution and Expression

Regional Localization

The M5 receptor exhibits a distinctive distribution pattern in the brain, with highest expression in:

Substantia nigra pars compacta (SNc): High density of M5 receptors on dopaminergic neurons
Ventral tegmental area (VTA): Located in the mesolimbic pathway
Hippocampus: Particularly in CA1 and CA3 regions
Cortex: Layer-specific expression in pyramidal neurons
Striatum: Both in medium spiny neurons and interneurons
Hypothalamus: Especially in the supraoptic and paraventricular nuclei
Basal forebrain: Cholinergic neuron bodies

This distribution closely overlaps with dopaminergic pathways and regions involved in learning, memory, and movement control[@receptor].

Cellular Localization

At the cellular level, M5 receptors are found on:

Dopaminergic neurons in the substantia nigra and VTA
Pyramidal neurons in cortex and hippocampus
GABAergic interneurons
[Astrocytes](/cell-types/astrocytes) Microglia (at lower levels)

The presynaptic localization on dopamine terminals in the striatum and cortex is particularly important for understanding M5's role in modulating dopamine release.

Expression Changes in Disease

Post-mortem studies have revealed altered M5 receptor expression in neurodegenerative diseases:

Alzheimer's Disease:

Reduced M5 receptor binding in hippocampus and cortex
Correlation with cholinergic neuron loss
Correlation with cognitive decline severity

Parkinson's Disease:

Altered M5 expression in the basal ganglia
Changes in striatal M5 receptor density
Potential compensatory changes in response to dopamine loss

Role in Alzheimer's Disease

Cholinergic Hypothesis and M5

The cholinergic hypothesis of AD posits that loss of basal forebrain cholinergic neurons and subsequent deficits in acetylcholine signaling contribute to cognitive impairment. While M1 and M4 receptors have been the primary focus of therapeutic development, M5 receptors also play important roles in cholinergic signaling in brain regions affected by AD[@cholinergic].

Amyloid-Beta Interactions

M5 receptor signaling can influence amyloid precursor protein (APP) processing and amyloid-beta (Aβ) production:

BACE1 regulation: Muscarinic receptor activation can modulate β-secretase expression
APP processing: Gq-coupled receptors influence α- and β-secretase activity
Aβ clearance: May affect mechanisms of Aβ clearance including autophagy

The relationship between M5 and Aβ is complex and context-dependent, with both protective and potentially detrimental effects reported.

Tau Pathology

M5 receptor activation may influence tau phosphorylation through:

Modulation of tau kinases (GSK3β, CDK5)
Effects on protein phosphatases
Influence on cellular stress responses

Synaptic Function and Cognition

M5 receptors contribute to cognitive function through:

Hippocampal plasticity: Modulation of long-term potentiation (LTP)
Cortical processing: Influence on working memory and attention
Learning and memory: Involvement in various memory paradigms

Studies using M5 knockout mice show subtle cognitive deficits, though less severe than M1 receptor knockout, suggesting M5 plays a modulatory rather than essential role in cognition.

Neuroprotection

M5 receptor activation can provide neuroprotective effects through:

Anti-apoptotic signaling: Akt pathway activation
Oxidative stress reduction: Decreased ROS production
Mitochondrial protection: Improved mitochondrial function
Anti-inflammatory effects: Modulation of glial activation

These neuroprotective properties suggest potential therapeutic applications for M5-targeted compounds in AD[@felder2001].

Role in Parkinson's Disease

Basal Ganglia Circuitry

Parkinson's disease is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to dysfunction of the basal ganglia motor circuit. Muscarinic receptors, including M5, play important roles in modulating this circuitry[@muscarinica].

In the basal ganglia, M5 receptors are located on:

Dopaminergic nerve terminals (presynaptic)
Medium spiny neurons (postsynaptic)
Cholinergic interneurons (striatal aspiny neurons)

The interaction between cholinergic and dopaminergic systems in the striatum is critical for motor control, and M5 receptors represent a key interface between these neurotransmitter systems.

Dopamine Release Modulation

M5 receptors on dopaminergic terminals modulate dopamine release:

Presynaptic modulation: M5 activation can enhance dopamine release
Frequency-dependent effects: Different effects at low vs. high firing rates
Interaction with D1/D2 receptors: Complex interplay in striatal signaling

This modulation has implications for both PD symptoms and levodopa-induced dyskinesias[@berger2002].

Motor Control

Within the basal ganglia, M5 influences motor control:

Mermaid diagram (expand to render)

Therapeutic Implications

The role of M5 in PD has several therapeutic implications:

Anticholinergic therapy: Classic treatments use non-selective muscarinic antagonists

M5-selective targeting: Potential for subtype-specific approaches

Dyskinesia management: M5 modulation may influence levodopa-induced dyskinesias

Current PD treatments that target muscarinic receptors include:

Trihexyphenidyl (Artane)
Benztropine (Cogentin)
Procyclidine (Kemadrin)

These non-selective antagonists provide symptomatic relief but have significant side effects due to actions at multiple muscarinic subtypes.

Therapeutic Targeting

M5 as a Drug Target

The M5 receptor represents a potential therapeutic target for:

Neurodegenerative Diseases:

Alzheimer's disease: Cognitive enhancement, neuroprotection
Parkinson's disease: Motor symptom modulation, dyskinesia management

Other CNS Disorders:

Schizophrenia: Modulation of dopaminergic and cholinergic systems
Addiction: Influence on mesolimbic dopamine pathways
Depression: Potential mood effects through neurotransmitter modulation

Challenges in M5-Targeted Drug Development

Several challenges have hindered M5-targeted drug development:

Lack of selective ligands: Limited availability of M5-specific compounds

Expression in peripheral organs: Side effects from peripheral actions

Complex pharmacology: Multiple signaling pathways and tissue-specific effects

Blood-brain barrier penetration: CNS delivery challenges

Current Approaches

Allosteric Modulation:
Allosteric modulators offer subtype selectivity advantages:

Positive allosteric modulators (PAMs) enhance agonist responses
Negative allosteric modulators (NAMs) reduce agonist effects
May provide more selective targeting than orthosteric ligands

M1/M4 Selective Agonists:
Some compounds show preferential activity at M1 and M4:

Xanomeline: M1/M4 preferring, in clinical trials for AD
Talsaclidine: M1 preferring

Novel M5-Selective Compounds:
Several research programs have developed M5-selective compounds in preclinical development[@conn2009].

Genetic Studies

CHRM5 Polymorphisms

Genetic studies have examined CHRM5 polymorphisms in neurodegenerative diseases:

AD association studies: Some variants show suggestive associations
PD association studies: Limited evidence for major effects
Cognitive function: Genetic variation may influence cognitive trajectories

Animal Models

Knockout mice:
M5 knockout mice show:

Reduced dopamine release in striatum
Altered locomotor responses
Subtle cognitive changes
Normal development and viability

Transgenic models:
M5 overexpression studies show:

Enhanced dopamine release
Altered behavioral responses
Modified drug responses

These models have helped elucidate M5 function in vivo.

Research Directions

Unresolved Questions

Why is M5 the least studied muscarinic receptor? - Historical challenges with selective ligands

What are the distinct functions of M5 compared to other subtypes? - Need for comparative studies

Can M5-selective modulation provide therapeutic benefits? - Clinical validation needed

What are the long-term effects of M5-targeted interventions? - Safety and efficacy concerns

Emerging Research Areas

Optogenetics: Using light to control M5-expressing circuits
Designer receptors: Chemogenetic (DREADD) approaches
Single-cell RNAseq: Understanding M5 expression at cellular resolution
Protein structures: Cryo-EM structures of M5 bound to various ligands

External Links

[NCBI Gene: CHRM5](https://www.ncbi.nlm.nih.gov/gene/1129)
[UniProt: P08912](https://www.uniprot.org/uniprot/P08912)
[IUPHAR: CHRM5](https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=65)
[PubMed: CHRM5](https://pubmed.ncbi.nlm.nih.gov/?term=CHRM5+muscarinic+receptor)
[Ensembl: CHRM5](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000121966)

References

[Birdsall & Lazareno, Muscarinic acetylcholine receptors (1999)](https://pubmed.ncbi.nlm.nih.gov/10491354/)

[Rosenblaum et al., Gq-coupled muscarinic receptors (2002)](https://pubmed.ncbi.nlm.nih.gov/11888521/)

[Weiner & Brann, M5 receptor distribution (2003)](https://pubmed.ncbi.nlm.nih.gov/12711704/)

[Cai et al., Cholinergic therapy in Alzheimer's disease (2004)](https://pubmed.ncbi.nlm.nih.gov/14598217/)

[Michell et al., Muscarinic antagonists in Parkinson's disease (2005)](https://pubmed.ncbi.nlm.nih.gov/15654760/)

[Felder et al., Therapeutic opportunities for muscarinic receptors (2001)](https://doi.org/10.1021/jm000279a020)

[Eglen et al., Muscarinic receptor ligands and CNS disorders (2001)](https://doi.org/10.1016/S0165-6147(00)01736-X)

[Hedlund & Gundlach, Muscarinic receptors in basal ganglia (2002)](https://doi.org/10.1007/s007020200067)

[Levey et al., Muscarinic receptor proteins in brain (1993)](https://pubmed.ncbi.nlm.nih.gov/8386254/)

[Volpicelli & Levey, Muscarinic receptor subtypes in cortex and hippocampus (2003)](https://doi.org/10.1016/j.brainres.2003.08.064)

[Wess, Muscarinic receptor knockout mice phenotypes (2004)](https://doi.org/10.1146/annurev.pharmtox.44.101802.121752)

[Berger et al., Acetylcholine and dopamine interactions (2002)](https://pubmed.ncbi.nlm.nih.gov/12097644/)

[Zhang et al., Muscarinic receptor-mediated dopamine release (2002)](https://pubmed.ncbi.nlm.nih.gov/11978834/)

[Toth et al., Muscarinic modulation of NMDA responses (2001)](https://pubmed.ncbi.nlm.nih.gov/11378148/)

[Conn et al., Subtype-selective muscarinic modulators (2009)](https://doi.org/10.1016/j.tips.2008.12.003)

[Langmead et al., Muscarinic receptors as CNS drug targets (2008)](https://doi.org/10.1016/j.pharmthera.2007.10.009)

[Bray et al., M5 muscarinic receptors and neuronal survival (2003)](https://pubmed.ncbi.nlm.nih.gov/14533277/)

[Olsson et al., Muscarinic receptors in neurodegenerative diseases (2006)](https://doi.org/10.1016/j.brainresrev.2005.10.001)

[Caccin et al., Muscarinic receptors in Alzheimer's disease (2011)](https://pubmed.ncbi.nlm.nih.gov/21143141/)

[Fisher, Cholinergic modulation of APP processing (2012)](https://doi.org/10.1007/s00702-011-0713-7)

Summary

CHRM5 encodes the M5 muscarinic acetylcholine receptor, a GPCR with important roles in dopaminergic and cholinergic systems of the brain. While less studied than other muscarinic subtypes, M5 receptor signaling influences neurotransmitter release, synaptic plasticity, and neuroprotection in regions affected by Alzheimer's and Parkinson's disease. The development of M5-selective compounds represents a promising avenue for therapeutic intervention in neurodegenerative diseases.

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CHRM5

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📊 Evidence Profile

Evidence Balance

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Outgoing

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📗 Cite This Artifact

CHRM5 Gene

CHRM5 Gene — Muscarinic Acetylcholine Receptor 5

Introduction

CHRM5 Gene — Muscarinic Acetylcholine Receptor 5

Introduction

Receptor Pharmacology and Signaling

G Protein Coupling

Downstream Pathways

Ligand Pharmacology

Brain Distribution and Expression

Regional Localization

Cellular Localization

Expression Changes in Disease

Role in Alzheimer's Disease

Cholinergic Hypothesis and M5

Amyloid-Beta Interactions

Tau Pathology

Synaptic Function and Cognition

Neuroprotection

Role in Parkinson's Disease

Basal Ganglia Circuitry

Dopamine Release Modulation

Motor Control

Therapeutic Implications

Therapeutic Targeting

M5 as a Drug Target

Challenges in M5-Targeted Drug Development

Current Approaches

Genetic Studies

CHRM5 Polymorphisms

Animal Models

Research Directions

Unresolved Questions

Emerging Research Areas

See Also

External Links

References

Summary

💬 Discussion