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¹ Department of Anatomy and Neurobiology, Colorado State University, Fort Collins, CO 80523
² Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642

Address correspondence to Kurt G. Beam, Department of Anatomy and Neurobiology, Colorado State University, 1345 Center Avenue, Fort Collins, CO 80523. Fax: (970) 491-7907; E-mail: kbeam{at}lamar.colostate.edu

Strong depolarization and dihydropyridine agonists potentiate inward currents through native L-type Ca²⁺ channels, but the effect on outward currents is less clear due to the small size of these currents. Here, we examined potentiation of wild-type _1C and two constructs bearing mutations in conserved glutamates in the pore regions of repeats II and IV (E2A/E4A-_1C) or repeat III (E3K-_1C). With 10 mM Ca²⁺ in the bath and 110 mM Cs⁺ in the pipette, these mutated channels, expressed in dysgenic myotubes, produced both inward and outward currents of substantial amplitude. For both the wild-type and mutated channels, we observed strong inward rectification of potentiation: strong depolarization had little effect on outward tail currents but caused the inward tail currents to be larger and to decay more slowly. Similarly, exposure to DHP agonist increased the amplitude of inward currents and decreased the amplitude of outward currents through both E2A/E4A-_1C and E3K-_1C. As in the absence of drug, strong depolarization in the presence of dihydropyridine agonist had little effect on outward tail currents but increased the amplitude and slowed the decay of inward tail currents. We tested whether cytoplasmic Mg²⁺ functions as the blocking particle responsible for the rectification of potentiated L-type Ca²⁺ channels. However, even after complete removal of cytoplasmic Mg²⁺, (-)BayK 8644 still potentiated inward current and partially blocked outward current via E2A/E4A-_1C. Although zero Mg²⁺ did not reveal potentiation of outward current by DHP agonist, it did have two striking effects, (a) a strong suppression of decay of both inward and outward currents via E2A/E4A-_1C and (b) a nearly complete elimination of depolarization-induced potentiation of inward tail currents. These results can be explained by postulating that potentiation exposes a binding site in the pore to which an intracellular blocking particle can bind and produce inward rectification of the potentiated channels.

Key Words: voltage-dependent potentiation • dihydropyridine agonist • gating

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