A Selectivity Filter Gate Controls Voltage-Gated Calcium Channel Calcium-Dependent Inactivation.

Affiliation

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 93858-2330, USA; Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 93858-2330, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 93858-2330, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 93858-2330, USA; Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: [Email]

Abstract

Calcium-dependent inactivation (CDI) is a fundamental autoregulatory mechanism in CaV1 and CaV2 voltage-gated calcium channels. Although CDI initiates with the cytoplasmic calcium sensor, how this event causes CDI has been elusive. Here, we show that a conserved selectivity filter (SF) domain II (DII) aspartate is essential for CDI. Mutation of this residue essentially eliminates CDI and leaves key channel biophysical characteristics untouched. DII mutants regain CDI by placing an aspartate at the analogous SF site in DIII or DIV, but not DI, indicating that CaV SF asymmetry is key to CDI. Together, our data establish that the CaV SF is the CDI endpoint. Discovery of this SF CDI gate recasts the CaV inactivation paradigm, placing it squarely in the framework of voltage-gated ion channel (VGIC) superfamily members in which SF-based gating is important. This commonality suggests that SF inactivation is an ancient process arising from the shared VGIC pore architecture.

Keywords

Ca(V)1.2,Ca(V)1.3,Ca(V)2.1,calcium-dependent inactivation,electrophysiology,selectivity filter,voltage-gated calcium channel,voltage-gated ion channel,

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