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RECEPTORS AND SIGNAL TRANSDUCTION

The monomeric G proteins AGS1 and Rhes selectively influence Gi-dependent signaling to modulate N-type (Ca_V2.2) calcium channels

Department of Biology, Utah State University, Logan, Utah

Submitted 1 July 2008 ; accepted in final form 17 September 2008

Activator of G protein Signaling 1 (AGS1) and Ras homologue enriched in striatum (Rhes) define a new group of Ras-like monomeric G proteins whose signaling properties and physiological roles are just beginning to be understood. Previous results suggest that AGS1 and Rhes exhibit distinct preferences for heterotrimeric G proteins, with AGS1 selectively influencing Gi and Rhes selectively influencing Gs. Here, we demonstrate that AGS1 and Rhes trigger nearly identical modulation of N-type Ca²⁺ channels (Ca_V2.2) by selectively altering Gi-dependent signaling. Whole-cell currents were recorded from HEK293 cells expressing Ca_V2.2 and Gi- or Gs-coupled receptors. AGS1 and Rhes reduced basal current densities and triggered tonic voltage-dependent (VD) inhibition of Ca_V2.2. Additionally, each protein attenuated agonist-initiated channel inhibition through Gi-coupled receptors without reducing channel inhibition through a Gs-coupled receptor. The above effects of AGS1 and Rhes were blocked by pertussis toxin (PTX) or by expression of a Gβ-sequestering peptide (masGRK3ct). Transfection with HRas, KRas2, Rap1A-G12V, Rap2B, Rheb2, or Gem failed to duplicate the effects of AGS1 and Rhes on Ca_V2.2. Our data provide the first demonstration that AGS1 and Rhes exhibit similar if not identical signaling properties since both trigger tonic Gβ signaling and both attenuate receptor-initiated signaling by the Gβ subunits of PTX-sensitive G proteins. These results are consistent with the possibility that AGS1 and Rhes modulate Ca²⁺ influx through Ca_V2.2 channels under more physiological conditions and thereby influence Ca²⁺-dependent events such as neurosecretion.

voltage-gated calcium channels; Ras-like; Dexras1; Dexras2; RASD1; RASD2