Alternatively spliced α1G (Cav3.1) intracellular loops promote specific T-type Ca2+ channel gating properties

At least three genes encode T-type calcium channel a, subunits, and identification of cDNA transcripts provided evidence that molecular diversity of these channels can be further enhanced by alternative splicing mechanisms, especially for the alpha (1G) subunit (Ca(V)3.1). Using whole-cell patch-clamp procedures, we have investigated the electrophysiological properties of five isoforms of the human alpha (1G) subunit that display a distinct III-IV 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 expressed in HEK-293 cells. We report that insertion e within the II-III linker specifically modulates inactivation, steady-state kinetics, and modestly recovery from inactivation, whereas alternative splicing within the III-IV linker affects preferentially kinetics and voltage dependence of activation, as well as deactivation and inactivation. By using voltage-clamp protocols mimicking neuronal activities, such as cerebellar train of action potentials and thalamic low-threshold spike, we describe that inactivation properties of alpha (1G-a) and alpha (1G-ae) isoforms can support channel behaviors reminiscent to those described in native neurons. Altogether, these data demonstrate that expression of distinct variants for the T-type alpha (1G) subunit can account for specific low-voltage-activated currents observed in neuronal tissues.