CHRM5

CHRM5 encodes the M5 muscarinic acetylcholine receptor, a Gq/11-coupled GPCR that transduces acetylcholine signaling in distinct physiological contexts including mesolimbic reward circuitry, bladder smooth muscle, and bone marrow vasculature. In the ventral subiculum, CHRM5 is expressed on neurons projecting to the nucleus accumbens shell, where it modulates initial motivation for alcohol self-administration, and its mRNA is upregulated by chronic alcohol exposure (PMID:33942300). In bone marrow arterial endothelium, CHRM5 activates eNOS–nitric oxide signaling to maintain arterial dilation and sinusoidal shear stress required for hematopoietic stem cell transendothelial migration and homing, a pathway that deteriorates with age-related acetylcholine depletion (PMID:40593589).

1. 1999 Medium

   Establishing the chromosomal location of Chrm5 was a prerequisite for candidate-gene studies; mapping to mouse chromosome 2 and sequencing in the El2 epilepsy model excluded Chrm5 as the El2 causative locus.

   Evidence Restriction fragment length variant analysis in interspecific backcross mice and Chrm5 sequencing in El2 mutants

   PMID:10549128

   Open questions at the time

   • No functional consequence of Chrm5 loss was tested in this study
   • Human chromosomal synteny not explicitly confirmed here
2. 2012 Medium

   Testing whether Chrm5 contributes to oviductal ciliary function revealed that it is not expressed in oviductal epithelium and its deletion does not affect ciliary beat frequency, defining a tissue where Chrm5 is dispensable.

   Evidence RT-PCR of laser-microdissected oviductal epithelium and ciliary beat frequency measurement in Chrm1/3/4/5 knockout mice

   PMID:22302687

   Open questions at the time

   • Other potential Chrm5-expressing tissues were not surveyed in parallel
   • Whether Chrm5 plays a role in other mucosal ciliated epithelia was not tested
3. 2021 Medium

   Demonstrating that Chrm5 in the ventral subiculum modulates alcohol self-administration via projections to the nucleus accumbens shell provided the first circuit-level mechanism linking M5 receptors to reward-driven behavior.

   Evidence Intra-vSub infusion of the M5 negative allosteric modulator ML375 combined with retrograde tracing and RNAscope in alcohol-preferring rats

   PMID:33942300

   Open questions at the time

   • Genetic loss-of-function (knockout or knockdown) in the vSub has not been performed
   • Downstream signaling cascade from M5 activation in vSub neurons is undefined
   • Generalizability beyond alcohol-preferring rat strain not established
4. 2023 Low

   Identification of a homozygous CHRM5 missense variant in a neurogenic bladder patient, combined with prior Chrm5-KO bladder overactivity data, implicated CHRM5 in human bladder contractile regulation, though functional validation of the variant itself was inconclusive.

   Evidence Exome sequencing of patient; expression analysis in murine and human bladder; reference to Chrm5 KO mouse phenotype

   PMID:37213061

   Open questions at the time

   • In vitro functional assays of the p.Gln184Arg variant did not demonstrate a clear mechanistic effect
   • Causality between CHRM5 and neurogenic bladder not established in additional families or rescue experiments
   • Signaling pathway downstream of CHRM5 in bladder smooth muscle is uncharacterized
5. 2025 Medium

   Revealing that non-neurogenic acetylcholine signals through Chrm5 on arterial endothelium to activate eNOS–NO–dependent arterial dilation established a vascular mechanism by which M5 receptors support hematopoietic stem cell homing, and showed that age-related acetylcholine loss disrupts this axis.

   Evidence In vivo imaging, pharmacological manipulation, metabolomics, and functional HSPC homing assays in mice

   PMID:40593589

   Open questions at the time

   • Endothelial-specific Chrm5 knockout has not been reported
   • Whether Chrm5 agonism can rescue age-related homing defects is untested
   • Relative contribution of Chrm5 versus other muscarinic receptors on bone marrow endothelium is unclear

• The intracellular signaling cascades downstream of CHRM5 in each expressing tissue (brain, bladder, vasculature) remain incompletely defined, and no structural model of CHRM5-specific ligand recognition or allosteric modulation has been reported.
• No cryo-EM or crystal structure of CHRM5 is available
• Tissue-specific Chrm5 conditional knockouts have not been generated
• Endogenous signaling complexes (scaffolds, effectors) interacting with CHRM5 are uncharacterized