FAMILIAL HEMIPLEGIC MIGRAINE MUTATIONS CHANGE ALPHA(1A) CA2+ CHANNEL KINETICS

Missense mutations in the pore-forming human alpha(1A) subunit of neur onal P/Q-type Ca2+ channels are associated with familial hemiplegic mi graine (FHM). The pathophysiological consequences of these mutations a re unknown. We have introduced the four single mutations reported for the human alpha(1A) subunit into the conserved rabbit alpha(1A) (R192Q , T666M, V714A, and I1819L) and investigated possible changes in chann el function after functional expression of mutant subunits in Xenopus laevis oocytes. Changes in channel gating were observed for mutants T6 66M, V714A, and I1819L but not for R192Q, Ba2+ current (I-Ba) inactiva tion was slightly faster in mutants T666M and V714A than in wild type. The time course of recovery from channel inactivation was slower than in wild type in T666M and accelerated in V714A and I1819L. As a conse quence, accumulation of channel inactivation during a train of 1-Hz pu lses was more pronounced for mutant T666M and less pronounced for V714 A and I1819A. Our data demonstrate that three of the four FHM mutation s, located at the putative channel pore, alter inactivation gating and provide a pathophysiological basis for the postulated neuronal instab ility in patients with FHM.