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© The Rockefeller University Press, 0022-1295/1998//807/ $5.00
Journal of General Physiology, Volume 111, Number 6, 1998

Article

Inactivation of Gating Currents of L-Type Calcium Channels

Specific Role of the {alpha}2{delta} Subunit



Roman Shirokov, Gonzalo Ferreira, Jianxun Yi, and Eduardo Ríos

From the Department of Molecular Biophysics and Physiology, Rush University School of Medicine, Chicago, Illinois 60612

In studies of gating currents of rabbit cardiac Ca channels expressed as {alpha}1C/β2a or {alpha}1C/β2a/{alpha}2{delta} subunit combinations in tsA201 cells, we found that long-lasting depolarization shifted the distribution of mobile charge to very negative potentials. The phenomenon has been termed charge interconversion in native skeletal muscle (Brum, G., and E. Ríos. 1987. J. Physiol. (Camb.). 387:489–517) and cardiac Ca channels (Shirokov, R., R. Levis, N. Shirokova, and E. Ríos. 1992. J. Gen. Physiol. 99:863–895). Charge 1 (voltage of half-maximal transfer, V1/2 ~= 0 mV) gates noninactivated channels, while charge 2 (V1/2 ~= –90 mV) is generated in inactivated channels. In {alpha}1C/β2a cells, the available charge 1 decreased upon inactivating depolarization with a time constant {tau} ~= 8, while the available charge 2 decreased upon recovery from inactivation (at –200 mV) with {tau} ~= 0.3 s. These processes therefore are much slower than charge movement, which takes <50 ms. This separation between the time scale of measurable charge movement and that of changes in their availability, which was even wider in the presence of {alpha}2{delta}, implies that charges 1 and 2 originate from separate channel modes. Because clear modal separation characterizes slow (C-type) inactivation of Na and K channels, this observation establishes the nature of voltage-dependent inactivation of L-type Ca channels as slow or C-type. The presence of the {alpha}2{delta} subunit did not change the V1/2 of charge 2, but sped up the reduction of charge 1 upon inactivation at 40 mV (to {tau} ~= 2 s), while slowing the reduction of charge 2 upon recovery ({tau} ~= 2 s). The observations were well simulated with a model that describes activation as continuous electrodiffusion (Levitt, D. 1989. Biophys. J. 55:489–498) and inactivation as discrete modal change. The effects of {alpha}2{delta} are reproduced assuming that the subunit lowers the free energy of the inactivated mode.

Key Words: cardiac muscle • heterologous expression • continuum model of gating • charge interconversion • charge immobilization

Address correspondence to Roman Shirokov, Department of Molecular Biophysics and Physiology, Rush University School of Medicine, 1750 W. Harrison Street, Suite 1279JS, Chicago, IL 60612. Fax: 312-942-8711; E-mail: rshiroko{at}rush.edu


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