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I. The Slow and the Fast Gating Modes and their Modulation by ß Subunits

Siro Luvisetto¹, Tommaso Fellin¹, Michele Spagnolo¹, Bruno Hivert^1,2, Paul F. Brust^3,4, Michael M. Harpold³, Kenneth A. Stauderman^3,5, Mark E. Williams^3,6, and Daniela Pietrobon¹

¹ Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Institute of Neuroscience, University of Padova, 35121 Padova, Italy
² Department of Biology, Faculte des Sciences de Luminy, 13288 Marseille, cedex 9, France
³ SIBIA Neurosciences, La Jolla, CA 92037
⁴ Senomyx Inc., La Jolla, CA 92037
⁵ Neurogenetics Inc., La Jolla, CA 92037
⁶ Merck Research Labs, San Diego, CA 92121

Address correspondence to Daniela Pietrobon, Dept. of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy. Fax: 39-049-8276049. email: daniela.pietrobon{at}unipd.it

The single channel gating properties of human Ca_V2.1 (P/Q-type) calcium channels and their modulation by the auxiliary ß_1b, ß_2e, ß_3a, and ß_4a subunits were investigated with cell-attached patch-clamp recordings on HEK293 cells stably expressing human Ca_V2.1 channels. These calcium channels showed a complex modal gating, which is described in this and the following paper (Fellin, T., S. Luvisetto, M. Spagnolo, and D. Pietrobon. 2004. J. Gen. Physiol. 124:463–474). Here, we report the characterization of two modes of gating of human Ca_V2.1 channels, the slow mode and the fast mode. A channel in the two gating modes differs in mean closed times and latency to first opening (both longer in the slow mode), in voltage dependence of the open probability (larger depolarizations are necessary to open the channel in the slow mode), in kinetics of inactivation (slower in the slow mode), and voltage dependence of steady-state inactivation (occurring at less negative voltages in the slow mode). Ca_V2.1 channels containing any of the four ß subtypes can gate in either the slow or the fast mode, with only minor differences in the rate constants of the transitions between closed and open states within each mode. In both modes, Ca_V2.1 channels display different rates of inactivation and different steady-state inactivation depending on the ß subtype. The type of ß subunit also modulates the relative occurrence of the slow and the fast gating mode of Ca_V2.1 channels; ß_3a promotes the fast mode, whereas ß_4a promotes the slow mode. The prevailing mode of gating of Ca_V2.1 channels lacking a ß subunit is a gating mode in which the channel shows shorter mean open times, longer mean closed times, longer first latency, a much larger fraction of nulls, and activates at more positive voltages than in either the fast or slow mode.

Key Words: Ca²⁺ channel • gating mode • synaptic transmission • familial hemiplegic migraine • auxiliary subunit

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