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Volume 17, Number 18, Issue of September 15, 1997 pp. 6884-6891
Copyright ©1997 Society for Neuroscience

Dissection of Functional Domains of the Voltage-Dependent Ca²⁺ Channel ₂ Subunit

Received April 29, 1997; revised June 9, 1997; accepted June 30, 1997.

Ricardo Felix¹, Christina A. Gurnett¹, Michel De Waard², and Kevin P. Campbell¹

¹ Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City, Iowa 52242, and ² Institut National de la Santé et de la Recherche Médicale U464, Institut Jean Roche, Faculté de Médicine Nord, 13916 Marseille 20, France

Coexpression of the cloned voltage-dependent Ca²⁺ channel ₂ subunit with the pore-forming ₁ subunit results in a significant increase in macroscopic current amplitude. To gain insight into the mechanism underlying this interaction, we have examined the regulatory effect of either the ₂ complex or the  subunit on the Ca²⁺ channel ₁ subunit. Transient transfection of tsA201 cells with the cardiac L-type _1C subunit alone resulted in the expression of inward voltage-activated currents as well as measurable [³H]-PN200-110 binding to membranes from transfected cells. Coexpression of the ₂ subunit significantly increased the macroscopic current amplitude, altered the voltage dependence and the kinetics of the current, and enhanced [³H]-PN200-110 binding. Except for the increase in amplitude, coexpression of the  subunit reproduced entirely the effects of the full-length ₂ subunit on the biophysical properties of the _1C currents. However, no effect on specific [³H]-PN200-110 binding was observed on  subunit coexpression. Likewise, profound effects on current kinetics of the neuronal _1A subunit were observed on coexpression of the ₂ complex in Xenopus oocytes. Furthermore, by using a chimeric strategy, we localized the region involved in this regulation to the transmembrane domain of the  subunit. These data strongly suggest that the molecular determinants involved in ₂ regulation are conserved across L-type and non-L type Ca²⁺ channels. Taken together, our results indicate that the region of the ₂ subunit involved in the modulation of the gating properties of the high voltage-activated calcium channels is localized in the  domain of the protein. In contrast, the level of membrane expression of functional channels relies on the presence of the ₂ domain of the ₂ complex.

Key words: L-type Ca channel; P/Q-type Ca channels; ₂ subunit; subunit; transient expression; tsA201 cells; dihydropyridine binding

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