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PNAS 100 (12): 7337-7342

Copyright © 2003 by the National Academy of Sciences.


RGS3 mediates a calcium-dependent termination of G protein signaling in sensory neurons

Patrizia Tosetti*, Narendra Pathak, Michele H. Jacob, and Kathleen Dunlap{dagger}

Department of Neuroscience, Tufts University School of Medicine and Molecular Cardiology Research Institute, New England Medical Center, Boston, MA 02111

Accepted for publication April 23, 2003.

Received for publication March 31, 2003.

Abstract: G proteins modulate synaptic transmission. Regulators of G protein signaling (RGS) proteins accelerate the intrinsic GTPase activity of Gα subunits, and thus terminate G protein activation. Whether RGS proteins themselves are under cellular control is not well defined, particularly in native cells. In dorsal root ganglion neurons overexpressing RGS3, we find that G protein signaling is rapidly terminated (or "desensitized") by calcium influx through voltage-gated channels. This rapid desensitization is most likely mediated by direct binding of calcium to RGS3, as deletion of an EF-hand domain in RGS3 abolishes both the desensitization (observed physiologically) and a calcium-RGS3 interaction (observed in a gel-shift assay). A naturally occurring variant of RGS3 that lacks the EF hand neither binds calcium nor produces rapid desensitization, giving rise instead to a slower calcium-dependent desensitization that is attenuated by a calmodulin antagonist. Thus, activity-evoked calcium entry in sensory neurons may provide differential control of G protein signaling, depending on the isoform of RGS3 expressed in the cells. In complex neural circuits subjected to abundant synaptic inhibition by G proteins (as occurs in dorsal spinal cord), rapid termination of inhibition by electrical activity by EF hand-containing RGS3 may ensure the faithful transmission of information from the most active sensory inputs.

{dagger} To whom correspondence should be addressed. E-mail: kathleen.dunlap{at}

* Present address: Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unit 29, 163 Avenue de Luminy, BP13, 13273 Marseille Cedex 09, France.

Edited by Charles F. Stevens, The Salk Institute for Biological Studies, La Jolla, CA

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: RGS, regulators of G protein signaling; DRG, dorsal root ganglion; BAPTA, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; GABA, {gamma}-aminobutyric acid; CaM, calmodulin; PIP3, phosphatidylinositol 3,4,5-trisphosphate; HA, hemagglutinin.

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