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CaVbeta subunit-mediated up-regulation of CaV2.2 currents triggered by D2 dopamine receptor activation

C Cantí1, A C Dolphin

  • 1Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. c.canti@ucl.ac.uk

Neuropharmacology
|October 8, 2003
PubMed

Insights

Voltage-dependent calcium channels (CaV2.2) show increased activity during G-protein inhibition, potentiated by G-protein coupled receptors. This run-up depends on accessory subunits and enhanced G-protein GTPase activity, not second messengers.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biophysics

Background:

  • Voltage-dependent calcium channels (VDCCs) are modulated by G-proteins and kinases.
  • Ca(V)2.2 channels are crucial for neuronal excitability and neurotransmitter release.

Purpose of the Study:

  • To investigate the potentiation of Ca(V)2.2 channel run-up during G-protein coupled receptor (GPCR) activation.
  • To elucidate the mechanisms underlying this potentiation, including the roles of accessory subunits and G-protein signaling.

Main Methods:

  • Xenopus oocyte expression system to study Ca(V)2.2 channel function.
  • Electrophysiological recordings to measure channel activity.
  • Co-expression of GPCRs and G-protein subunits to investigate signaling pathways.

Main Results:

  • Ca(V)2.2 channels exhibited a sustained, irreversible run-up in activity.
  • GPCR activation potentiated this run-up, associated with a hyperpolarization of activation voltage.
  • Beta subunits promoted, while alpha2delta subunits opposed the current increase.
  • Over-expression of Galpha(o) or Galpha-transducin reduced agonist-mediated up-regulation.
  • No evidence for second messenger involvement was found.

Conclusions:

  • GPCR activation enhances Ca(V)2.2 channel run-up via increased endogenous Galpha subunit GTPase activity.
  • This potentiation is mediated by accessory Ca(V)beta subunits.
  • Potential mechanisms include increased Ca(V)beta-alpha1 subunit association or channel trafficking to the plasma membrane.

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