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Journal Article
Research Support, Non-U.S. Gov't
Negatively charged residues in the first extracellular loop of the L-type Ca V 1.2 channel anchor the interaction with the Ca V α2δ1 auxiliary subunit.
Journal of Biological Chemistry 2017 October 21
Voltage-gated L-type CaV 1.2 channels in cardiomyocytes exist as heteromeric complexes. Co-expression of CaV α2δ1 with CaV β/CaV α1 proteins reconstitutes the functional properties of native L-type currents, but the interacting domains at the CaV 1.2/CaV α2δ1 interface are unknown. Here, a homology-based model of CaV 1.2 identified protein interfaces between the extracellular domain of CaV α2δ1 and the extracellular loops of the CaV α1 protein in repeats I (IS1S2 and IS5S6), II (IIS5S6), and III (IIIS5S6). Insertion of a 9-residue hemagglutinin epitope in IS1S2, but not in IS5S6 or in IIS5S6, prevented the co-immunoprecipitation of CaV 1.2 with CaV α2δ1. IS1S2 contains a cluster of three conserved negatively charged residues Glu-179, Asp-180, and Asp-181 that could contribute to non-bonded interactions with CaV α2δ1. Substitutions of CaV 1.2 Asp-181 impaired the co-immunoprecipitation of CaV β/CaV 1.2 with CaV α2δ1 and the CaV α2δ1-dependent shift in voltage-dependent activation gating. In contrast, single substitutions in CaV 1.2 in neighboring positions in the same loop (179, 180, and 182-184) did not significantly alter the functional up-regulation of CaV 1.2 whole-cell currents. However, a negatively charged residue at position 180 was necessary to convey the CaV α2δ1-mediated shift in the activation gating. We also found a more modest contribution from the positively charged Arg-1119 in the extracellular pore region in repeat III of CaV 1.2. We conclude that CaV 1.2 Asp-181 anchors the physical interaction that facilitates the CaV α2δ1-mediated functional modulation of CaV 1.2 currents. By stabilizing the first extracellular loop of CaV 1.2, CaV α2δ1 may up-regulate currents by promoting conformations of the voltage sensor that are associated with the channel's open state.
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