The role of a voltage-dependent Ca 2+ channel intracellular linker: A structure-function analysis

Lior Almagor, Orna Chomsky-Hecht, Adva Ben-Mocha, Doran Hendin-Barak, Nathan Dascal, Joel A. Hirsch

Research output: Contribution to journalArticlepeer-review

Abstract

Voltage-dependent calcium channels (VDCCs) allow the passage of Ca 2+ ions through cellular membranes in response to membrane depolarization. The channel pore-forming supunit,α1, and a regulatory supunit (Ca Vβ) form a high affinity complex where Ca Vβ binds to a α1 interacting domain in the intracellular linker between α1 membrane domains I and II (I-II linker). We determined crystal structures of Ca Vβ2 functional core in complex with the Ca V1.2 and Ca V2.2 I-II linkers to a resolution of 1.95 and 2.0 Å, respectively. Structural differences between the highly conserved linkers, important for coupling Ca Vβ to the channel pore, guided mechanistic functional studies. Electrophysiological measurements point to the importance of differing linker structure in both Ca V1 and 2 suptypes with mutations affecting both voltage- and calcium-dependent inactivation and voltage dependence of activation. These linker effects persist in the absence of Ca Vβ, pointing to the intrinsic role of the linker in VDCC function and suggesting that I-II linker structure can serve as a brake during inactivation.

Original languageEnglish
Pages (from-to)7602-7613
Number of pages12
JournalJournal of Neuroscience
Volume32
Issue number22
DOIs
StatePublished - 30 May 2012

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