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II. The b Mode and Reversible Uncoupling of Inactivation

Tommaso Fellin, Siro Luvisetto, Michele Spagnolo, and Daniela Pietrobon

Department of Biomedical Sciences and Consiglio Nazionale delle Ricerche Institute of Neuroscience, University of Padova, 35121 Padova, Italy

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 were investigated with cell-attached patch-clamp recordings on HEK293 cells stably expressing these calcium channels. Human Ca_V2.1 channels showed a complex modal gating, which is described in this and the preceding paper (Luvisetto, S., T. Fellin, M. Spagnolo, B. Hivert, P.F. Brust, M.M. Harpold, K.A. Stauderman, M.E. Williams, and D. Pietrobon. 2004. J. Gen. Physiol. 124:445–461). Here, we report the characterization of the so-called b gating mode. A Ca_V2.1 channel in the b gating mode shows a bell-shaped voltage dependence of the open probability, and a characteristic low open probability at high positive voltages, that decreases with increasing voltage, as a consequence of both shorter mean open time and longer mean closed time. Reversible transitions of single human Ca_V2.1 channels between the b gating mode and the mode of gating in which the channel shows the usual voltage dependence of the open probability (nb gating mode) were much more frequent (time scale of seconds) than those between the slow and fast gating modes (time scale of minutes; Luvisetto et al., 2004), and occurred independently of whether the channel was in the fast or slow mode. We show that the b gating mode produces reversible uncoupling of inactivation in human Ca_V2.1 channels. In fact, a Ca_V2.1 channel in the b gating mode does not inactivate during long pulses at high positive voltages, where the same channel in both fast-nb and slow-nb gating modes inactivates relatively rapidly. Moreover, a Ca_V2.1 channel in the b gating mode shows a larger availability to open than in the nb gating modes. Regulation of the complex modal gating of human Ca_V2.1 channels could be a potent and versatile mechanism for the modulation of synaptic strength and plasticity as well as of neuronal excitability and other postsynaptic Ca²⁺-dependent processes.

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

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