Familial hemiplegic migraine mutations change alpha1A Ca2+ channel kinetics.
Missense mutations in the pore-forming human alpha1A subunit of neuronal P/Q-type Ca2+ channels are associated with familial hemiplegic migraine (FHM). The pathophysiological consequences of these mutations are unknown. We have introduced the four single mutations reported for the human alpha1A subunit into the conserved rabbit alpha1A (R192Q, T666M, V714A, and I1819L) and investigated possible changes in channel function after functional expression of mutant subunits in Xenopus laevis oocytes. Changes in channel gating were observed for mutants T666M, V714A, and I1819L but not for R192Q. Ba2+ current (IBa) inactivation 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 consequence, accumulation of channel inactivation during a train of 1-Hz pulses was more pronounced for mutant T666M and less pronounced for V714A and I1819A. Our data demonstrate that three of the four FHM mutations, located at the putative channel pore, alter inactivation gating and provide a pathophysiological basis for the postulated neuronal instability in patients with FHM.
Kraus
R L
RL
Institut fur Biochemische Pharmakologie, Peter-Mayr-Strasse 1, A-6020 Innsbruck, Austria.
Sinnegger
M J
MJ
Glossmann
H
H
Hering
S
S
Striessnig
J
J
D000818:Animals; D001464:Barium / Q000493:pharmacokinetics; D015220:Calcium Channels / Q000235:genetics* / Q000502:physiology; D020864:Calcium Channels, N-Type; D004594:Electrophysiology; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D007700:Kinetics; D008881:Migraine Disorders / Q000235:genetics* / Q000503:physiopathology; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D011817:Rabbits; D014162:Transfection / Q000235:genetics; D014982:Xenopus laevis
D001464:Barium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type