Inhibition of N and PQ calcium channels by calcium entry through L channels in chromaffin cells

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Why adrenal chromaffin cells express various subtypes of voltage-dependent Ca(2+) channels and whether a given channel is specialized to perform a specific function are puzzling and unanswered questions. In this study, we have used the L Ca(2+) channel activator FPL64176 (FPL) to test the hypothesis that enhanced Ca(2+) entry through this channel favors the inhibition of N and PQ channels in voltage-clamped bovine adrenal chromaffin cells. Using 2 mM Ca(2+) as charge carrier and under the perforated-patch configuration (PPC) of the patch-clamp technique, FPL caused a paradoxical inhibition of the whole-cell inward Ca(2+) current (I (Ca)). Such inhibition turned on into an augmentation upon cell loading with EGTA-AM. Also, under the whole-cell configuration (WCC) of the patch-clamp technique, FPL decreased I (Ca) in the absence of EGTA from the pipette solution and increased the current in its presence. Using 2 mM Ba(2+) as charge carrier, FPL augmented the Ba(2+) current under both recording conditions, WCC and PPC. FPL augmented the residual current remaining after blockade of N and PQ channels with omega-conotoxin MVIIC or by holding the membrane potential at -50 mV. The data support the view that Ca(2+) entering the cell through the lesser inactivating L channels serves to modulate the more inactivating N and PQ channels. They also suggest a close colocalization of L and N/PQ Ca(2+) channels. This kind of L channel specialization may be relevant to cell excitability, exocytosis, and cell survival mechanisms.