Heterotrimeric G protein αi2 Sequesters RasGAP to Control Neutrophil Sensitivity and Chemotaxis

G protein–coupled receptors (GPCRs) direct neutrophil chemotaxis through heterotrimeric G proteins, yet the downstream effectors of the predominant G a i isoform, G a i2, remain incompletely defined. Here we identify the Ras GTPase-activating protein CAPRI (RASA4) as a functional effector of G a i2 that links GPCR signaling to Ras adaptation. Using AlphaFold3-based structural modeling and binding free-energy calculations and experimental verification, we reveal that constitutively active and structurally altered G a i2 mutants (Q205L and T182A) exhibit enhanced binding to CAPRI. Neutrophils expressing these mutants display elevated basal Ras activity, heightened sensitivity to chemoattractant, and improved chemotaxis in low- or subsensitive-concentration gradients. However, these cells exhibit excessive Ras activation and impaired chemotaxis at high, saturating chemoattractant concentrations, while maintaining near-normal responses at intermediate concentrations. These results reveal an upward shift in the concentration range for efficient chemotaxis. Our findings not only establish a previously unrecognized G a i2–CAPRI signaling axis that tunes Ras adaptation but also define a mechanism by which heterotrimeric G proteins calibrate leukocyte navigation across diverse chemoattractant gradients.