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 CaV2.2 and Gi- or Gs-coupled receptors. AGS1 and Rhes reduced basal current densities and triggered tonic voltage-dependent (VD) inhibition of Ca_V2.2. Furthermore, 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 G-sequestering peptide (masGRK3ct). Transfection with HRas, KRas2, Rap1A-G12V, Rap2B, Rheb2 or Gem failed to mimic 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 G signaling and both attenuate receptor-initiated signaling by the G 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.