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G-proteins modulate cumulative inactivation of N-type (Cav2.2) calcium channels

Sarah McDavid1, Kevin P M Currie

  • 1Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|December 22, 2006
PubMed

Insights

G-proteins reduce the inactivation of calcium channels (Ca-channels), impacting calcium ion (Ca2+) entry. This novel finding reveals how G-protein-coupled receptors regulate Ca2+-dependent cellular functions like hormone release.

Area of Science:

  • Cellular Neuroscience
  • Molecular Pharmacology
  • Ion Channel Physiology

Background:

  • Voltage-gated calcium channels (Ca-channels) precisely regulate cellular functions, including neurotransmitter and hormone release.
  • G-protein betagamma subunits (Gbetagamma) inhibit Ca2+ entry by altering Ca-channel gating states.
  • The modulation of Ca-channel inactivation by G-proteins remains poorly understood due to complex inactivation mechanisms and confounding facilitation effects.

Purpose of the Study:

  • To investigate whether G-proteins modulate the inactivation of N-type (Ca(V)2.2) voltage-gated calcium channels.
  • To characterize the novel effects of G-proteins on Ca-channel inactivation kinetics.
  • To explore the implications for G-protein-coupled receptor signaling in regulating Ca2+-dependent cellular processes.

Main Methods:

  • Utilized low-frequency trains of action potential-like waveforms (APW) to activate Ca-channel currents (I(Ca)) and circumvent facilitation.
  • Activated endogenous G-proteins and expressed wild-type or mutant Gbetagamma subunits in human embryonic kidney 293 cells.
  • Investigated I(Ca) inactivation in response to G-protein activation and P2Y receptor stimulation in adrenal chromaffin cells.

Main Results:

  • Activation of endogenous G-proteins significantly reduced both Ca2+-dependent and voltage-dependent inactivation of recombinant I(Ca).
  • Expression of wild-type Gbetagamma mimicked this reduction in inactivation, whereas a Gbetagamma mutant with reduced channel affinity did not.
  • Stimulation of P2Y receptors in adrenal chromaffin cells also decreased I(Ca) inactivation, consistent with G-protein involvement.

Conclusions:

  • G-proteins exert a novel modulatory effect on Ca-channel inactivation, decreasing both Ca2+-dependent and voltage-dependent components.
  • This G-protein-mediated reduction in inactivation is dependent on Gbetagamma subunit interaction with Ca-channels.
  • The findings provide new insights into how G-protein-coupled receptors control Ca2+ influx and subsequent Ca2+-dependent events, such as hormone and neurotransmitter release.

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