Channels (Austin) 2010 Jan 01;41:42-50. doi: 10.4161/chan.4.1.10562.

Swapping the I-II intracellular linker between L-type CaV1.2 and R-type CaV2.3 high-voltage gated calcium channels exchanges activation attributes.

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Calcium entry through voltage-gated calcium channels (VGCC) initiates diverse cellular functions. VGCC pore-forming subunit (Ca(V)alpha(1)) contains four homology repeats, each encompassing a voltage sensor and a pore domain. Three main classes of Ca(V)alpha(1) subunits have been described, Ca(V)1, Ca(V)2 and Ca(V)3 that differ in their voltage-dependence of activation and in the extent in which this process is modulated by the auxiliary beta-subunit (Ca(V)beta). Association of Ca(V)beta induces a coil-to-helix conformation of the I-II intracellular linker joining the first and second repeat of Ca(V)alpha(1) that is thought to be crucial for modulation of channel function. When expressed in Xenopus laevis oocytes in the absence of Ca(V)beta, the voltage to reach 50% activation (V(0.5)) for Ca(V)1.2 and Ca(V)2.3 differs by more than 60 mV and the channel current-carrying capacity by more than thirty-fold. Here we report that the difference in V(0.5) is reduced to about 30 mV and the current-carrying capacity becomes virtually identical when the I-II linkers of Ca(V)1.2 and Ca(V)2.3 are swapped. Co-expression with Ca(V)beta increases the current-carrying capacity of chimeric channels by the same extent, while the difference in V(0.5) with respect to their corresponding parental channels vanishes. Our findings indicate that Ca(V)beta modulatory potency is determined by both, the nature of the I-II linker and the pore-forming subunit background. Moreover, they demonstrate that the I-II linker encodes self-reliant molecular determinants for channel activation and suggest that besides the secondary structure adopted by this segment upon Ca(V)beta association, its chemical nature is as well relevant.

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Species referenced: Xenopus laevis
Genes referenced: cacna1c cacna1e cacnb3 cav1 cav2