Evolutionary insights into T-type Ca(2+) 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.