ARMH2

ARMH2 is a cytosolic subunit of the sperm-specific CatSper Ca²⁺ channel complex, where it forms a ternary subcomplex with EFCAB9 and CATSPERζ that stabilizes the linear nanodomain arrangement of CatSper along the sperm flagellum (PMID:41271765). ARMH2 regulates the pH and Ca²⁺ sensitivity of CatSper channel activation, and its genetic ablation in mice causes defective CatSper activation, asthenozoospermia, and subfertility (PMID:41271765).

1. 2025 High

   Resolving the molecular identity and structural role of ARMH2 within the CatSper complex established it as a cytosolic subunit that forms a ternary subcomplex with EFCAB9 and CATSPERζ, stabilizes CatSper nanodomain architecture, and tunes channel gating — filling the gap in understanding how accessory subunits regulate sperm Ca²⁺ signaling.

   Evidence Cryo-EM structure, mass spectrometry, AlphaFold prediction, coevolutionary analysis, and Armh2-knockout mouse phenotyping in sperm

   PMID:41271765

   Open questions at the time

   • Atomic-resolution details of the ARMH2–EFCAB9–CATSPERζ interface and how conformational changes transmit pH/Ca²⁺ signals to the pore remain unresolved
   • Whether ARMH2 has any function outside sperm or the CatSper complex is unknown
   • Human genetic validation linking ARMH2 mutations to male infertility has not been reported

• The precise allosteric mechanism by which ARMH2 modulates CatSper pH and Ca²⁺ sensitivity, and whether ARMH2 loss-of-function variants contribute to human male infertility, remain open questions.
• No reconstituted electrophysiology of the ARMH2-containing subcomplex to dissect gating contributions
• No human patient cohort data linking ARMH2 variants to asthenozoospermia or infertility