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Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel

M L Schiff1, D P Siderovski, J D Jordan

  • 1Department of Pharmacology, Mount Sinai School of Medicine, New York, New York 10029, USA.

Nature
|December 29, 2000
PubMed

Insights

Regulators of G-protein signaling (RGS12) interact with calcium channels in neurons. This interaction, mediated by RGS12

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Signaling

Background:

  • GABA(B) receptors inhibit N-type calcium channels in neurons via a tyrosine-kinase pathway.
  • This inhibition is voltage-independent and transient.
  • Regulators of G-protein signaling (RGS) proteins modulate G-protein coupled pathways.

Purpose of the Study:

  • To investigate the role of RGS12 in GABA(B) receptor-mediated calcium channel inhibition.
  • To elucidate the mechanism by which RGS12 regulates the duration of this signaling pathway.

Main Methods:

  • Utilized primary dorsal root ganglion neurons in culture.
  • Investigated tyrosine-kinase-dependent complex formation between RGS12 and calcium channels.
  • Employed fusion proteins to assess the function of different RGS12 domains (RGS, PDZ, PTB).

Main Results:

  • Endogenous agonist stimulation induced a tyrosine-kinase-dependent complex of RGS12 and calcium channels.
  • The PTB domain of RGS12 was crucial for altering the termination rate of the GABA(B) signal.
  • RGS and PDZ domains of RGS12 did not show significant effects on signal termination.

Conclusions:

  • RGS12 is a multifunctional protein that directly interacts with tyrosine-phosphorylated calcium channels via its PTB domain.
  • RGS12 plays a key role in regulating the time course of GABA(B) receptor-mediated calcium channel inhibition.
  • Recruitment of RGS proteins to G-protein effectors may be a novel mechanism for terminating G-protein signaling.

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