The Role of a Voltage-Dependent Ca 2+ Channel Intracellular Linker: A Structure-Function Analysis

• Published in: The Journal of neuroscience 2012-05, Vol.32 (22), p.7602-7613
• Main Authors: Almagor, Lior, Chomsky-Hecht, Orna, Ben-Mocha, Adva, Hendin-Barak, Doran, Dascal, Nathan, Hirsch, Joel A.
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.5727-11.2012

Voltage-dependent calcium channels (VDCCs) allow the passage of Ca 2+ ions through cellular membranes in response to membrane depolarization. The channel pore-forming subunit, α1, and a regulatory subunit (Ca V β) form a high affinity complex where Ca V β 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 V β2 functional core in complex with the Ca V 1.2 and Ca V 2.2 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 V β to the channel pore, guided mechanistic functional studies. Electrophysiological measurements point to the importance of differing linker structure in both Ca V 1 and 2 subtypes with mutations affecting both voltage- and calcium-dependent inactivation and voltage dependence of activation. These linker effects persist in the absence of Ca V β, 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.