文章基本信息

标题：A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis
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作者：Selma A. Serra ; Ester Cuenca-León ; Artur Llobet 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：4
页码：1672-1677
DOI：10.1073/pnas.0908359107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca2+ channel {alpha}1A subunit (CACNA1A) locate to the pore and voltage sensor regions and normally involve gain-of-channel function. We now report on a mutation identified in the first intracellular loop of CACNA1A ({alpha}1A(A454T)) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree. {alpha}1A(A454T) channels showed weakened regulation of voltage-dependent steady-state inactivation by CaV{beta} subunits. More interestingy, A454T mutation suppressed P/Q channel modulation by syntaxin 1A or SNAP-25 and decreased exocytosis. Our findings reveal the importance of I-II loop structural integrity in the functional interaction between P/Q channel and proteins of the vesicle-docking/fusion machinery, and that genetic variation in CACNA1A may be not only a cause but also a modifier of migraine phenotype.
关键词：CaV 2.1 (P/Q) channels ; SNARE proteins ; migraine with aura