Convergent structural and functional evolution of CALHM ion channel with connexins and pannexins-innexins

CALHM1 (calcium homeostasis modulator 1) is a plasma membrane ion channel that mediates neuronal excitability in response to changes in extracellular Ca2+ concentration. Six human CALHM homologs exist with no homology to other proteins, although CALHM1 is conserved across \u3e20 species. Here we demonstrate that CALHM1 shares functional and quaternary, tertiary, and secondary structural similarities with connexins and evolutionarily distinct innexins and their vertebrate pannexin homologs. A CALHM1 channel is a hexamer, comprising six monomers, each of which possesses four transmembrane domains, cytoplasmic amino- and carboxyl termini, an amino terminal helix, and conserved extracellular cysteines. The estimated pore diameter of CALHM1 is ∼14 Å, enabling permeation of large charged molecules. Thus, CALHMs, connexins and pannexin/innexins are three protein families structurally related by homoplasy with shared and distinct functional properties