Evolutionary insights into T-type Ca2+ channel structure, function, and ion selectivity from the Trichoplax adhaerens homologue

Four-domain voltage-gated Ca 2+ (Ca v ) channels play fundamental roles in the nervous system, but little is known about when or how their unique properties and cellular roles evolved. Of the three types of metazoan Ca v channels, Ca v 1 (L-type), Ca v 2 (P/Q-, N- and R-type) and Ca v 3 (T-type), Ca v 3 channels are optimized for regulating cellular excitability because of their fast kinetics and low activation voltages. These same properties permit Ca v 3 channels to drive low-threshold exocytosis in select neurons and neurosecretory cells. Here, we characterize the single T-type calcium channel from Trichoplax adhaerens (TCa v 3), an early diverging animal that lacks muscle, neurons, and synapses. Co-immunolocalization using antibodies against TCa v 3 and neurosecretory cell marker complexin labeled gland cells, which are hypothesized to play roles in paracrine signaling. Cloning and in vitro expression of TCa v 3 reveals that, despite roughly 600 million years of divergence from other T-type channels, it bears the defining structural and biophysical features of the Ca v 3 family. We also characterize the channel’s cation permeation properties and find that its pore is less selective for Ca 2+ over Na + compared with the human homologue Ca v 3.1, yet it exhibits a similar potent block of inward Na + current by low external Ca 2+ concentrations (i.e., the Ca 2+ block effect). A comparison of the permeability features of TCa v 3 with other cloned channels suggests that Ca 2+ block is a locus of evolutionary change in T-type channel cation permeation properties and that mammalian channels distinguish themselves from invertebrate ones by bearing both stronger Ca 2+ block and higher Ca 2+ selectivity. TCa v 3 is the most divergent metazoan T-type calcium channel and thus provides an evolutionary perspective on Ca v 3 channel structure–function properties, ion selectivity, and cellular physiology.