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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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gamma1-dependent down-regulation of recombinant voltage-gated Ca2+ channels

Alejandro Sandoval1, Jyothi Arikkath, Eduardo Monjaraz

  • 1.Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute Cinvestav-IPN, Avenida IPN 2508, Colonia Zacatenco, Mexico City, DF CP 07300, Mexico.

Cellular and Molecular Neurobiology
|October 16, 2007
PubMed

Insights

The auxiliary gamma1 subunit reduces CaV1.1 protein expression, decreasing calcium (Ca2+) current density. This finding explains how gamma1 impacts skeletal muscle excitation-contraction coupling.

Area of Science:

  • Molecular biology
  • Cellular physiology
  • Ion channel biophysics

Background:

  • Voltage-gated Ca2+ (CaV) channels are crucial for cellular Ca2+ influx and cellular functions.
  • Skeletal muscle CaV channels involve CaV1.1, alpha2delta-1, beta1, and gamma1 subunits, acting as both channels and voltage sensors.
  • The role of the gamma1 subunit in CaV channel regulation is less understood compared to other subunits.

Purpose of the Study:

  • To investigate the regulatory role of the auxiliary gamma1 subunit on CaV channel expression and function.
  • To elucidate the impact of gamma1 co-expression on the ion-conducting CaV1.1 subunit.

Main Methods:

  • Western blotting to assess protein expression levels of CaV1.1.
  • Heterologous co-expression of gamma1 with CaV1.1 in HEK-293 cells.
  • Patch-clamp electrophysiology to measure Ca2+ currents through recombinant N-type CaV channels.

Main Results:

  • Co-expression of gamma1 with CaV1.1 significantly reduced CaV1.1 protein levels.
  • Gamma1 transfection drastically inhibited macroscopic currents through recombinant N-type CaV channels (CaV2.2/alpha2delta-1/beta3).
  • Reduced Ca2+ current density in myotubes from gamma1 null mice was observed.

Conclusions:

  • The auxiliary gamma1 subunit decreases the expression of the ion-conducting CaV1.1 subunit.
  • This reduction in CaV1.1 expression likely explains the observed decrease in Ca2+ current density upon gamma1 transfection.
  • Gamma1 plays a significant regulatory role in skeletal muscle CaV channel function.

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