PT - JOURNAL ARTICLE AU - Lior Almagor AU - Orna Chomsky-Hecht AU - Adva Ben-Mocha AU - Doran Hendin-Barak AU - Nathan Dascal AU - Joel A. Hirsch TI - The Role of a Voltage-Dependent Ca<sup>2+</sup> Channel Intracellular Linker: A Structure-Function Analysis AID - 10.1523/JNEUROSCI.5727-11.2012 DP - 2012 May 30 TA - The Journal of Neuroscience PG - 7602--7613 VI - 32 IP - 22 4099 - http://www.jneurosci.org/content/32/22/7602.short 4100 - http://www.jneurosci.org/content/32/22/7602.full SO - J. Neurosci.2012 May 30; 32 AB - Voltage-dependent calcium channels (VDCCs) allow the passage of Ca2+ ions through cellular membranes in response to membrane depolarization. The channel pore-forming subunit, α1, and a regulatory subunit (CaVβ) form a high affinity complex where CaVβ 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 CaVβ2 functional core in complex with the CaV1.2 and CaV2.2 I–II linkers to a resolution of 1.95 and 2.0 Å, respectively. Structural differences between the highly conserved linkers, important for coupling CaVβ to the channel pore, guided mechanistic functional studies. Electrophysiological measurements point to the importance of differing linker structure in both CaV1 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 CaVβ, 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.