Ca2+-sensitive regulation of E-type Ca2+ channel activity depends on an arginine-rich region in the cytosolic II–III loop

Ca 2 + -dependent regulation of L-type and P/Q-type Ca 2 + channel activity is an important mechanism to control Ca 2 + entry into excitable cells. Here we addressed the question whether the activity of E-type Ca 2 + channels can also be controlled by Ca 2 + . Switching from Ba 2 + to Ca 2 + as charge carrier increased within 50 s, the density of currents observed in HEK-293 cells expressing a human Ca v 2.3d subunit and slowed down the inactivation kinetics. Furthermore, with Ca 2 + as permeant ion, recovery from inactivation was accelerated, compared to the recovery process recorded under conditions where the accumulation of [Ca 2 + ] i was prevented. In a Ba 2 + containing bath solution the Ca 2 + -dependent changes of E-type channel activity could be induced by dialysing the cells with 1 μM free [Ca 2 + ] i suggesting that an elevation of [Ca 2 + ] i is responsible for these effects. Deleting 19 amino acids in the intracellular II-III linker (exon 19) as part of an arginine-rich region, severely impairs the Ca 2 + responsiveness of the expressed channels. Interestingly, deletion of an adjacent homologue arginine-rich region activates channel activity but now independently from [Ca 2 + ] i . As a positive feedback-regulation of channel activity this novel activation mechanism might determine specific biological functions of E-type Ca 2 + channels.