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The Journal of Neuroscience, March 1, 1999, 19(5):1610-1619

Functional Consequences of Mutations in the Human _1A Calcium Channel Subunit Linked to Familial Hemiplegic Migraine

Michael Hans¹, Siro Luvisetto², Mark E. Williams¹, Michele Spagnolo², A. Urrutia¹, Angelita Tottene², Paul F. Brust¹, Edwin C. Johnson¹, Michael M. Harpold¹, Kenneth A. Stauderman¹, and Daniela Pietrobon²

¹ SIBIA Neurosciences, La Jolla, California 92037-4641, and ² Department of Biomedical Sciences and National Research Council (Consiglio Nazionale delle Ricerche) Center of Biomembranes, University of Padova, 35121 Padova, Italy

Mutations in _1A, the pore-forming subunit of P/Q-type calcium channels, are linked to several human diseases, including familial hemiplegic migraine (FHM). We introduced the four missense mutations linked to FHM into human _1A-2 subunits and investigated their functional consequences after expression in human embryonic kidney 293 cells. By combining single-channel and whole-cell patch-clamp recordings, we show that all four mutations affect both the biophysical properties and the density of functional channels. Mutation R192Q in the S4 segment of domain I increased the density of functional P/Q-type channels and their open probability. Mutation T666M in the pore loop of domain II decreased both the density of functional channels and their unitary conductance (from 20 to 11 pS). Mutations V714A and I1815L in the S6 segments of domains II and IV shifted the voltage range of activation toward more negative voltages, increased both the open probability and the rate of recovery from inactivation, and decreased the density of functional channels. Mutation V714A decreased the single-channel conductance to 16 pS. Strikingly, the reduction in single-channel conductance induced by mutations T666M and V714A was not observed in some patches or periods of activity, suggesting that the abnormal channel may switch on and off, perhaps depending on some unknown factor. Our data show that the FHM mutations can lead to both gain- and loss-of-function of human P/Q-type calcium channels.

Key words: calcium channel; familial hemiplegic migraine; cerebellar ataxia; _1A subunit; mutation; channelopathy

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1951610-10$05.00/0

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