The tumor suppressor eIF3e mediates calcium-dependent internalization of the L-type calcium channel CaV1.2.
Voltage-gated calcium channels (VGCCs) convert electrical activity into calcium (Ca2+) signals that regulate cellular excitability, differentiation, and connectivity. The magnitude and kinetics of Ca2+ signals depend on the number of VGCCs at the plasma membrane, but little is known about the regulation of VGCC surface expression. We report that electrical activity causes internalization of the L-type Ca2+ channel (LTC) CaV1.2 and that this is mediated by binding to the tumor suppressor eIF3e/Int6 (eukaryotic initiation factor 3 subunit e). Using total internal reflection microscopy, we identify a population of CaV1.2 containing endosomes whose rapid trafficking is strongly regulated by Ca2+. We define a domain in the II-III loop of CaV1.2 that binds eIF3e and is essential for the activity dependence of both channel internalization and endosomal trafficking. These findings provide a mechanism for activity-dependent internalization and trafficking of CaV1.2 and provide a tantalizing link between Ca2+ homeostasis and a mammalian oncogene.
Green
Eric M
EM
Department of Neurobiology, Stanford University, 299 Campus Drive, Fairchild Research Building D227, Stanford, CA 94305, USA.
Barrett
Curtis F
CF
Bultynck
Geert
G
Shamah
Steven M
SM
Dolmetsch
Ricardo E
RE
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D034284:Dynamin I / Q000235:genetics / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D004622:Embryo, Mammalian; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D011189:Potassium Chloride / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection / Q000379:methods; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D002118:Calcium; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D034284:Dynamin I; D039621:Eukaryotic Initiation Factor-3; D011189:Potassium Chloride; D020866:omega-Conotoxin GVIA
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