Conserved biophysical features of the Ca2 presynaptic Ca channel homologue from the early-diverging animal .

The dominant role of Ca2 voltage-gated calcium channels for driving neurotransmitter release is broadly conserved. Given the overlapping functional properties of Ca2 and Ca1 channels, and less so Ca3 channels, it is unclear why there have not been major shifts toward dependence on other Ca channels for synaptic transmission. Here, we provide a structural and functional profile of the Ca2 channel cloned from the early-diverging animal , which lacks a nervous system but possesses single gene homologues for Ca1-Ca3 channels. Remarkably, the highly divergent channel possesses similar features as human Ca2.1 and other Ca2 channels, including high voltage-activated currents that are larger in external Ba than in Ca; voltage-dependent kinetics of activation, inactivation, and deactivation; and bimodal recovery from inactivation. Altogether, the functional profile of Ca2 suggests that the core features of presynaptic Ca2 channels were established early during animal evolution, after Ca1 and Ca2 channels emerged via proposed gene duplication from an ancestral Ca1/2 type channel. The channel was relatively insensitive to mammalian Ca2 channel blockers ω-agatoxin-IVA and ω-conotoxin-GVIA and to metal cation blockers Cd and Ni Also absent was the capacity for voltage-dependent G-protein inhibition by co-expressed Gβγ subunits, which nevertheless inhibited the human Ca2.1 channel, suggesting that this modulatory capacity evolved via changes in channel sequence/structure, and not G proteins. Last, the channel was immunolocalized in cells that express an endomorphin-like peptide implicated in cell signaling and locomotive behavior and other likely secretory cells, suggesting contributions to regulated exocytosis.