Alternative splicing as a molecular switch for Ca2+/calmodulin-dependent facilitation of P/Q-type Ca2+ channels.
Alternative splicing of the P/Q-type channel (Ca(V)2.1) promises customization of the computational repertoire of neurons. Here we report that concerted splicing of its main alpha1A subunit, at both an EF-hand-like domain and the channel C terminus, controls the form of Ca2+-dependent facilitation (CDF), an activity-dependent enhancement of channel opening that is triggered by calmodulin. In recombinant channels, such alternative splicing switches CDF among three modes: (1) completely "ON" and driven by local Ca2+ influx through individual channels, (2) completely "OFF," and (3) partially OFF but inducible by elevated global Ca2+ influx. Conversion from modes 1 to 3 represents an unprecedented dimension of control. The physiological function of these variants is likely important, because we find that the distribution of EF-hand splice variants is strikingly heterogeneous in the human brain, varying both across regions and during development.
Chaudhuri
Dipayan
D
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Chang
Siao-Yun
SY
DeMaria
Carla D
CD
Alvania
Rebecca S
RS
Soong
Tuck Wah
TW
Yue
David T
DT
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002147:Calmodulin / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D005091:Exons / Q000235:genetics; D017136:Ion Transport / Q000187:drug effects; D007668:Kidney; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D014162:Transfection
D002118:Calcium; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002147:Calmodulin; D011993:Recombinant Fusion Proteins; C491528:Cacnb2 protein, mouse; C093712:Cacna1d protein, rat