Potentiation of the cardiac L-type Ca2+ channel (alpha(1C)) by dihydropyridine agonist and strong depolarization occur via distinct mechanisms

A defining property of L-type Ca2+ channels is their potentiation by both 1 ,4-diltydropyridine agonists and strong depolarization. In contrast, non-L- type channels are potentiated by neither agonist not-depolarization, sugges ting that these two processes may by linked. In this study, we have tested whether the mechanisms of agonist- and depolarization-induced potentiation in the cardiac L-type channel (alt;) are linked. We found that the mutant L -type channel GFP-alpha (1C)(TQ --> YM), bearing the mutations T1066Y and Q 1070M, was able to undergo depolarization-induced potentiation but not pote ntiation by agonist. Conversely, the chimeric channel GFP-CACC was potentia ted by agonist but not by strong depolarization. These data indicate that t he mechanisms of agonist-and depolarization-induced potentiation of alpha ( 1C) are distinct. Since neither GFP-CACC nor GFP-CCAA was potentiated signi ficantly by depolarization, no single repeat of alt; appears to be responsi ble for depolarization-induced potentiation. Surprisingly, GFP-CACC display ed a low estimated open probability similar to that of the alpha (1C) but c ould not support depolarization-induced potentiation, demonstrating that a relatively low open probability alone is not sufficient for depolarization- induced potentiation to occur. Thus, depolarization-induced potentiation ma y be a global channel property requiring participation from all four homolo gous repeats.