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

Neuron. 2019 Mar 20;101(6):1134-1149.e3. doi: 10.1016/j.neuron.2019.01.011. Epub 2019 Feb 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspartic Acid
  • Calcium / metabolism*
  • Calcium Channels, L-Type / genetics*
  • Calcium Channels, L-Type / metabolism
  • Calcium Channels, N-Type / genetics*
  • Calcium Channels, N-Type / metabolism
  • HEK293 Cells
  • Humans
  • Ion Channel Gating / genetics*
  • Mutation
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Xenopus laevis

Substances

  • Calcium Channels, L-Type
  • Calcium Channels, N-Type
  • L-type calcium channel alpha(1C)
  • voltage-dependent calcium channel (P-Q type)
  • Aspartic Acid
  • Calcium