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