CNNM1

CNNM1 (ACDP1) is a cytoplasmic-domain-bearing transmembrane protein of the CNNM/ACDP family that participates in divalent-cation homeostasis and signaling, with tissue expression restricted to brain and testis (PMID:12657465). In native rodent brain, CNNM1 is a stable component of high-molecular-weight complexes assembled with the ion channel-kinase TRPM7 and the small GTPase ARL15 (PMID:34766907). Within these complexes the CNNM cytoplasmic modules act through distinct surfaces: the CBS-pair domain modulates TRPM7 channel activity and is required for ARL15-mediated suppression of that channel, while the CNBH domain binds the TRPM7 kinase domain and enhances its catalytic activity in vitro (PMID:40962059). ARL15 binds the CNNM carboxy-terminal CBS domains and drives complex N-glycosylation of CNNMs, which negatively regulates Mg2+ transport (PMID:34089346). Independently of its channel-associated role, CNNM1 binds copper with high (nanomolar) affinity in the cytoplasm and alters cellular copper retention, consistent with a copper storage/chaperone function (PMID:17608643). In spermatogonial cells CNNM1 marks early c-KIT-/OCT3/4-positive cells and regulates cell-cycle progression, linking it to stem-cell self-renewal (PMID:27251091). Evidence from invertebrate orthologs places CNNM-mediated Mg2+ efflux upstream of AMPK-TORC1 and TORC2 signaling (PMID:27564576, PMID:38373693), but the membrane-transport activity of human CNNM1 itself has not been directly demonstrated in the available corpus.

1. 2003 Low

   Established the basic expression and subcellular distribution of the then-uncharacterized ACDP1 protein, defining where it might act.

   Evidence Immunofluorescence of permeabilized HeLa cells and tissue expression survey

   PMID:12657465

   Open questions at the time

   • Single immunofluorescence experiment with no functional readout
   • Nuclear localization conflicts with later plasma-membrane findings
   • No mechanism linked to the protein
2. 2004 Low

   Proposed an ion-transport role by linking ACDP/CNNM to the bacterial Mg2+/Co2+ efflux protein CorC and placing the mouse ortholog at the neuronal plasma membrane.

   Evidence Immunostaining of hippocampal neurons and sequence homology analysis

   PMID:14723793

   Open questions at the time

   • Homology inference, not direct transport assay for CNNM1
   • Localization conflicts with prior nuclear report
   • No functional validation of transport
3. 2005 Low

   Used a yeast family member to position CNNM-type proteins as a distinct branch of metal homeostasis acting independently of canonical metal transporters.

   Evidence Yeast MAM3 deletion, metal-tolerance assays, and epistasis with known transporters

   PMID:15498024

   Open questions at the time

   • Yeast ortholog, not mammalian CNNM1
   • Vacuolar localization may not map to human biology
   • Metal specificity for CNNM1 unresolved
4. 2007 Medium

   Showed that CNNM1 has a metal-binding biochemical activity distinct from cation efflux, identifying high-affinity copper binding and a copper-retention effect.

   Evidence Immobilized metal affinity chromatography, isothermal titration calorimetry, and cellular copper-retention assays

   PMID:17608643

   Open questions at the time

   • Single lab
   • Relationship between copper binding and Mg2+ biology unresolved
   • No structure of the copper-binding site
5. 2016 Medium

   Connected CNNM1 to a cellular phenotype, showing it regulates spermatogonial cell-cycle progression and associates with stemness downstream of differentiation cues.

   Evidence siRNA knockdown in GC1-spg cells with flow-cytometry cell-cycle analysis, IHC, and RT-PCR in mouse testis

   PMID:27251091

   Open questions at the time

   • Molecular link between CNNM1 ion/copper activity and cell cycle not defined
   • Single lab
   • No in vivo loss-of-function
6. 2016 Medium

   Demonstrated, via invertebrate genetics, that CNNM-mediated Mg2+ efflux acts upstream of AMPK-TORC1 signaling to control development.

   Evidence C. elegans cnnm-1/cnnm-3 mutant analysis, Mg2+ supplementation rescue, and aak-2 epistasis

   PMID:27564576

   Open questions at the time

   • Ortholog, not human CNNM1
   • Direct efflux activity of CNNM1 not measured
   • Phenotype reflects combined cnnm-1/cnnm-3 loss
7. 2021 High

   Identified CNNM1 as a native partner of TRPM7 and ARL15 in brain, establishing a physiological ternary complex that controls channel activity.

   Evidence Multi-epitope affinity purification and quantitative MS from rodent brain plus heterologous reconstitution and electrophysiology

   PMID:34766907

   Open questions at the time

   • CNNM1-specific contribution versus CNNM2-4 not separated
   • Stoichiometry and structure of the complex undefined
   • Functional consequence in neurons not shown
8. 2021 Medium

   Defined ARL15 as a CBS-domain-binding regulator that controls CNNM N-glycosylation and thereby Mg2+ transport.

   Evidence Co-immunoprecipitation, in silico modeling, immunocytochemistry, siRNA knockdown, and 25Mg2+ uptake assays

   PMID:34089346

   Open questions at the time

   • CNNM1-specific Mg2+ transport not isolated
   • Glycosylation site mapping incomplete
   • Single lab
9. 2024 Medium

   Extended the CNNM-Mg2+-mTOR axis to TORC2, showing excess Mg2+ from CNNM loss suppresses TORC2 and alters body size and dauer formation.

   Evidence C. elegans mutant and RNAi epistasis through gtl-1 and TORC2 components with dauer assays

   PMID:38373693

   Open questions at the time

   • Ortholog system
   • Effect attributed to Mg2+ accumulation rather than direct CNNM signaling
   • Human relevance not tested
10. 2025 Medium

    Dissected the domain logic of CNNM-TRPM7 coupling, separating complex assembly, channel modulation, and kinase enhancement onto distinct CNNM modules.

    Evidence Electrophysiology, in vitro kinase assays, binding assays, and domain truncation/mutagenesis

    PMID:40962059

    Open questions at the time

    • Mapping performed largely on CNNM2; CNNM1-specific behavior inferred
    • In vitro kinase enhancement is modest and not validated in cells
    • No structure of the assembled complex
11. 2025 Low

    Placed CNNM1 within GDNF-driven spermatogonial stem-cell self-renewal, linking its expression to proliferation and germ-cell development programs.

    Evidence Overexpression/knockdown in C18-4 cells with proteome profiling and cell-cycle analysis (preprint)

    Open questions at the time

    • Preprint, single lab
    • Proteome correlations without mechanistic node validation
    • No direct link to CNNM1 ion/copper activity

• Whether human CNNM1 itself directly transports Mg2+ (or another divalent cation) across membranes, and how its copper-binding, channel-modulating, and cell-cycle roles are mechanistically integrated, remains unresolved.
• No direct transport assay for human CNNM1
• No structure of CNNM1 alone or in the TRPM7/ARL15 complex
• Copper-chaperone and Mg2+/TRPM7 functions not reconciled