Three new familial hemiplegic migraine mutants affect P/Q-type Ca2+ channel kinetics

Missense mutations in the pore-forming human alpha(1A) subunit of neuronal P/Q-type Ca2+ channels are associated with familial hemiplegic migraine. We studied the functional consequences on P/Q-type Ca2+ channel function of t hree recently identified mutations, R583Q, D715E, and V1457L after introduc tion into rabbit alpha(1A) and expression in Xenopus laevis oocytes, The po tential for half-maximal channel activation of Ba2+ inward currents was shi fted by > 9 mV to more negative potentials in all three mutants. The potent ial for half-maximal channel inactivation was shifted by > 7 mV in the same direction in R583Q and D715E, Biexponential current inactivation during 3- s test pulses was significantly faster in D715E and slower in V1457L than i n wild type. Mutations R583Q and V1457L delayed the time course of recovery from channel inactivation. The decrease of peak current through R583Q (30. 2%) and D715E (30.1%) but not V1457L (18.7%) was more pronounced during l-H z trains of 15 100-ms pulses than in wild type (18,2%), Our data demonstrat e that the mutations R583Q, D715E, and V1457L, like the previously reported mutations T666M, V714A, and I1819L, affect P/Q-type Ca2+ channel gating, W e therefore propose that altered channel gating represents a common pathoph ysiological mechanism in familial hemiplegic migraine.