Pore-Blocking Effect of Isoindoline MDIMP on Voltage-Gated Calcium Channels

Abstract

Using the cut-open oocyte voltage clamp technique, we recorded ionic currents from channel complexes formed by a 1S /b 1a /stac3 with or without g 1 subunit, expressedin Xenopus oocytes. g 1 modified Ca V 1.1 voltage dependence of inactivation by decreasing the effective valence from 5.351.1e 0 (N=4) to 1.8750.2e 0 (N=4) and reducing the non-inactivating component of the ionic current following 10s pulses from $50% to $30%. In addition, we observed that g 1 coexpression did not affect voltage dependence of Ca V 1.1 activation (No g 1 : V half = 37.151.2mV, N=5, and with g 1 : V half = 40.051.5mV, N=4). However, when g 1 and a 2 d-1 were coexpressed, the voltage dependence of the Ca V 1.1 complex (a 1S /b 1a /a 2 d-1/g 1 /stac3) was facilitated. g 1 also strongly modulated the Ca V 1.2 channel isoform (a 1C / b 2b /a 2 d-1) by shifting the voltage dependence of channel inactivation by $20mV toward negative potentials. In conclusion, these studies have revealed the biophysical consequences of g 1 subunit association with two distinct human L-type channel isoforms in heterologous expression systems.