Alternatively spliced alpha(1G) (Ca(v)3.1) intracellular loops promote specific T-type Ca2+ channel gating properties

At least three genes encode T-type calcium channel a, subunits, and identif ication of cDNA transcripts provided evidence that molecular diversity of t hese channels can be further enhanced by alternative splicing mechanisms, e specially for the alpha (1G) subunit (Ca(V)3.1). Using whole-cell patch-cla mp procedures, we have investigated the electrophysiological properties of five isoforms of the human alpha (1G) subunit that display a distinct III-I V linker, namely, alpha (1G-a), alpha (1G-b) and alpha (1G-bc), as well as a distinct II-III linker, namely, alpha (1G-ae), alpha (1G-be), as expresse d in HEK-293 cells. We report that insertion e within the II-III linker spe cifically modulates inactivation, steady-state kinetics, and modestly recov ery from inactivation, whereas alternative splicing within the III-IV linke r affects preferentially kinetics and voltage dependence of activation, as well as deactivation and inactivation. By using voltage-clamp protocols mim icking neuronal activities, such as cerebellar train of action potentials a nd thalamic low-threshold spike, we describe that inactivation properties o f alpha (1G-a) and alpha (1G-ae) isoforms can support channel behaviors rem iniscent to those described in native neurons. Altogether, these data demon strate that expression of distinct variants for the T-type alpha (1G) subun it can account for specific low-voltage-activated currents observed in neur onal tissues.