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

Richard L. Kraus, Martina J. Sinnegger, Alexandra Koschak, Hartmut Glossmann, Stefania Stenirri, Paola Carrera, Jörg Striessnig

Research output: Contribution to journalArticle

Abstract

Missense mutations in the pore-forming human α(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 three recently identified mutations, R583Q, D715E, and V1457L after introduction into rabbit α(1A) and expression in Xenopus laevis oocytes. The potential for half-maximal channel activation of Ba2+ inward currents was shifted by > 9 mV to more negative potentials in all three mutants. The potential 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 in 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 1-Hz trains of 15 100-ms pulses than in wild type (18.2%). Our data demonstrate that the mutations R583Q, D715E, and V1457L, like the previously reported mutations T666M, V714A, and I1819L, affect P/Q-type Ca2+ channel gating. We therefore propose that altered channel gating represents a common pathophysiological mechanism in familial hemiplegic migraine.

Original languageEnglish
Pages (from-to)9239-9243
Number of pages5
JournalJournal of Biological Chemistry
Volume275
Issue number13
DOIs
Publication statusPublished - Mar 31 2000

ASJC Scopus subject areas

  • Biochemistry

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    Kraus, R. L., Sinnegger, M. J., Koschak, A., Glossmann, H., Stenirri, S., Carrera, P., & Striessnig, J. (2000). Three new familial hemiplegic migraine mutants affect P/Q-type Ca2+ channel kinetics. Journal of Biological Chemistry, 275(13), 9239-9243. https://doi.org/10.1074/jbc.275.13.9239