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FPL 64176 Modification of Ca_V1.2 L-Type Calcium Channels: Dissociation of Effects on Ionic Current and Gating Current

Stefan I. McDonough ^*, Yasuo Mori  and Bruce P. Bean 

^* Department of Neuroscience, Amgen Inc., Thousand Oaks, California; Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan; and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts

Correspondence: Address reprint requests to Dr. Bruce P. Bean, Dept. of Neurobiology, 200 Longwood Ave., Harvard Medical School, Boston, MA 02115. Tel.: 617-432-1139; Fax: 617-432-3057; E-mail: bruce_bean{at}hms.harvard.edu.

FPL 64176 (FPL) is a nondihydropyridine compound that dramatically increases macroscopic inward current through L-type calcium channels and slows activation and deactivation. To understand the mechanism by which channel behavior is altered, we compared the effects of the drug on the kinetics and voltage dependence of ionic currents and gating currents. Currents from a homogeneous population of channels were obtained using cloned rabbit Ca_V1.2 (_1C, cardiac L-type) channels stably expressed in baby hamster kidney cells together with ß_1a and ₂₁ subunits. We found a striking dissociation between effects of FPL on ionic currents, which were modified strongly, and on gating currents, which were not detectably altered. Inward ionic currents were enhanced 5-fold for a voltage step from –90 mV to +10 mV. Kinetics of activation and deactivation were slowed dramatically at most voltages. Curiously, however, at very hyperpolarized voltages (<–250 mV), deactivation was actually faster in FPL than in control. Gating currents were measured using a variety of inorganic ions to block ionic current and also without blockers, by recording gating current at the reversal potential for ionic current (+50 mV). Despite the slowed kinetics of ionic currents, FPL had no discernible effect on the fundamental movements of gating charge that drive channel gating. Instead, FPL somehow affects the coupling of charge movement to opening and closing of the pore. An intriguing possibility is that the drug causes an inactivated state to become conducting without otherwise affecting gating transitions.

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