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T-type calcium channel regulation by specific G-protein betagamma subunits

Joshua T Wolfe1, Hongge Wang, Jason Howard

  • 1Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.

Nature
|July 11, 2003
PubMed

Insights

Low-voltage-activated (LVA) calcium channels are selectively inhibited by specific G-protein beta2gamma2 subunits. This finding identifies the alpha1H calcium channel as a novel effector for G-protein signaling pathways.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Physiology

Background:

  • Low-voltage-activated (LVA) T-type calcium channels are crucial for neuronal excitability and hormone secretion.
  • G-protein-coupled receptor activation inhibits LVA channels via membrane-delimited signals, but the specific signaling molecules were unknown.

Purpose of the Study:

  • To identify the G-protein subunits responsible for inhibiting LVA T-type calcium channels.
  • To elucidate the mechanism of selective inhibition of specific LVA calcium channel isoforms.

Main Methods:

  • Site-directed mutagenesis of alpha1H (Ca(v)3.2) and alpha1G (Ca(v)3.1) calcium channel subunits.
  • Co-expression of channel subunits with G-protein beta2gamma2 subunits in a heterologous system.
  • Electrophysiological recordings to assess channel activity and modulation.

Main Results:

  • The beta2gamma2 subunit selectively inhibits alpha1H (Ca(v)3.2) but not alpha1G (Ca(v)3.1) LVA calcium channels.
  • A specific intracellular loop (connecting domains II and III) of alpha1H is essential for beta2gamma2-mediated inhibition.
  • Transferring this loop to alpha1G conferred beta2gamma2-dependent inhibition, demonstrating its critical role.
  • G-protein betagamma reduces channel activity independently of voltage, a novel mechanism for LVA channels.

Conclusions:

  • The alpha1H (Ca(v)3.2) calcium channel is a novel effector for G-protein beta2gamma2 subunits.
  • This study reveals a selective signaling pathway involving specific G-protein beta gamma combinations and LVA calcium channels.
  • The findings highlight the diverse mechanisms of G-protein modulation of ion channels.

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