RGS3 mediates a calcium-dependent termination of G protein signaling in sensory neurons.
G proteins modulate synaptic transmission. Regulators of G protein signaling (RGS) proteins accelerate the intrinsic GTPase activity of Galpha 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.
Tosetti
Patrizia
P
Department of Neuroscience, Tufts University School of Medicine and Molecular Cardiology Research Institute, New England Medical Center, Boston, MA 02111, USA.
Pathak
Narendra
N
Jacob
Michele H
MH
Dunlap
Kathleen
K
D000818:Animals; D001483:Base Sequence; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002642:Chick Embryo; D018076:DNA, Complementary / Q000235:genetics; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D014644:Genetic Variation; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020710:RGS Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D015220:Calcium Channels; D018076:DNA, Complementary; D020690:GTPase-Activating Proteins; D020710:RGS Proteins; D011994:Recombinant Proteins; C415085:Rgs3 protein, mouse; D005680:gamma-Aminobutyric Acid; D019204:GTP-Binding Proteins