CHRM5

CHRM5 (M5 muscarinic acetylcholine receptor) is a muscarinic receptor expressed across neural and vascular tissues where it transduces cholinergic signals into region-specific physiological outputs (PMID:33942300, PMID:40593589). In the ventral subiculum, CHRM5 is expressed on neurons projecting to the nucleus accumbens shell and controls initial motivation for alcohol self-administration: its mRNA is up-regulated after long-term alcohol consumption, and selective negative allosteric modulation reduces alcohol self-administration (PMID:33942300). In bone marrow arterial cells, CHRM5 operates through an eNOS-nitric oxide axis to drive arterial dilation, and this Chrm5-eNOS-NO signaling controls bone marrow blood flow and sinusoidal wall shear stress, thereby gating Piezo1 activation and hematopoietic stem/progenitor cell transendothelial migration and homing (PMID:40593589). CHRM5 is also expressed in bladder wall tissue, where Chrm5-knockout mice display bladder overactivity (PMID:37213061). Beyond these tissue-level roles, the receptor's downstream effector coupling has not been characterized in detail in the available corpus apart from the eNOS-NO axis (PMID:40593589).

1. 1999 Medium

   Establishing the chromosomal location of Chrm5 and testing it as a candidate disease gene clarified its genetic identity and excluded it as the El2 epilepsy locus.

   Evidence RFLV mapping in interspecific backcross mice and Chrm5 sequencing in El2 mutant mice

   PMID:10549128

   Open questions at the time

   • No functional or signaling role addressed
   • Mapping alone does not establish tissue expression or activity
2. 2002 Medium

   Radiation hybrid mapping localized rat Chrm5, extending its genetic characterization across species.

   Evidence Radiation hybrid mapping with rat RH map server

   PMID:12433399

   Open questions at the time

   • No functional consequence established
   • No link to a specific tissue or pathway
3. 2012 Medium

   Testing whether Chrm5 contributes to oviductal ciliary activity defined a tissue where the receptor is dispensable, sharpening the boundaries of its physiological role.

   Evidence RT-PCR of laser-microdissected oviductal epithelium and ciliary measurements in Chrm knockout mice

   PMID:22302687

   Open questions at the time

   • Negative result; does not identify where Chrm5 IS required
   • Compound knockout complicates attribution to Chrm5 specifically
4. 2021 Medium

   Linking CHRM5 in the ventral subiculum to alcohol motivation answered where and how the receptor modulates addiction-relevant behavior, identifying a defined neural circuit.

   Evidence RT-qPCR, retrograde tracing, RNAscope, and intra-vSub pharmacology with the negative allosteric modulator ML375 in alcohol-preferring rats

   PMID:33942300

   Open questions at the time

   • Downstream signaling within vSub neurons not defined
   • Mechanism linking M5 modulation to projection activity unresolved
   • Single lab
5. 2021 Low

   Identifying CHRM5 as a transcriptional target of myocardin-related factors hinted at how its expression is regulated in vascular smooth muscle.

   Evidence Forced MYOCD expression in human coronary artery SMCs with RNA-seq and RT-qPCR

   PMID:34539433

   Open questions at the time

   • Expression-level readout only without mechanistic follow-up for CHRM5
   • Direct promoter regulation not demonstrated
   • Functional consequence of increased CHRM5 not tested
6. 2023 Low

   Searching for a CHRM5 disease link in neurogenic bladder tested causality of a candidate variant, but the variant's pathogenicity could not be confirmed.

   Evidence Exome sequencing, bladder expression analysis, and in vitro functional studies of the p.Gln184Arg variant (inconclusive)

   PMID:37213061

   Open questions at the time

   • In vitro functional studies were negative/uninformative
   • Single case; expression data only correlative
   • Causality of CHRM5 in neurogenic bladder unresolved
7. 2025 Medium

   Defining a Chrm5-eNOS-NO axis in bone marrow arteries answered how cholinergic signaling mechanically regulates the hematopoietic niche through vascular dilation and shear stress.

   Evidence In vivo imaging, pharmacological manipulation, metabolomics, and signaling pathway dissection in mouse bone marrow

   PMID:40593589

   Open questions at the time

   • Direct receptor-eNOS coupling mechanism not structurally resolved
   • Replication not yet established
   • Source/regulation of non-neurogenic acetylcholine partially defined

• The proximal signal transduction events downstream of CHRM5 receptor activation across its varied tissues remain to be unified mechanistically.
• No structural model of CHRM5 in the corpus
• G-protein coupling and second-messenger cascades not directly characterized here
• Tissue-specific effector selection unexplained