Related Experiment Video

Updated: Jul 6, 2025

Determination of the Relative Cell Surface and Total Expression of Recombinant Ion Channels Using Flow Cytometry
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Asymmetric contribution of a selectivity filter gate in triggering inactivation of CaV1.3 channels

Pedro J Del Rivero Morfin1, Audrey L Kochiss1, Klaus R Liedl2

  • 1Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.

The Journal of General Physiology
|January 4, 2024
PubMed

Insights

Voltage-dependent and Ca2+-dependent inactivation in CaV channels are regulated by asymmetric conformational changes. These changes, particularly at the domain III-IV interface, impact channel pore conduction and CaM signaling, revealing crucial feedback mechanisms.

Area of Science:

  • Molecular and Cellular Biology
  • Biophysics
  • Neuroscience

Background:

  • Voltage-dependent inactivation (VDI) and Ca2+-dependent inactivation (CDI) are key feedback mechanisms controlling CaV channel function.
  • The precise mechanisms by which VDI and CDI obstruct ion flow through the CaV channel pore are not fully understood.

Purpose of the Study:

  • To investigate the role of asymmetric conformational changes in VDI and CDI of CaV channels.
  • To identify specific interfaces and residues critical for these inactivation processes.

Main Methods:

  • Site-directed mutagenesis of conserved tryptophan residues in CaV1.3 channel interfaces.
  • Molecular dynamics simulations to analyze conformational flexibility.
  • Electrophysiological recordings to assess VDI and CDI.

Main Results:

  • Mutagenesis of the CaV1.3 domain III-IV interface, but not other interfaces, significantly enhanced VDI.
  • Molecular dynamics simulations revealed that mutations in different selectivity filter interfaces differentially affect conformational flexibility.
  • Mutations in specific domains preferentially disrupted CaM-mediated CDI, indicating structural bifurcation of CaM signaling.

Conclusions:

  • Asymmetric conformational changes at specific CaV channel interfaces are critical for mediating both VDI and CDI.
  • The pseudotetrameric structure of the CaV pore domain plays a fundamental role in feedback inhibition.
  • Findings elucidate the structural basis of CaV channel inactivation and CaM signaling pathways.

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