Heterotrimeric G Protein and RasGAP Coupling Drives Adaptation During Chemotaxis

Chemotaxis enables eukaryotic cells to detect and migrate along extracellular chemoattractant gradients spanning several orders of magnitude. This remarkable dynamic range relies on adaptation, a process that allows cells to reset their signaling machinery while preserving sensitivity to incremental changes in stimulus intensity. Although numerous actin-dependent feedback mechanisms have been characterized, the molecular basis of adaptation within the actin-independent core gradient-sensing module remains poorly understood. Here we identify the Ras GTPase-activating protein C2GAP1 as a critical F-actin-independent effector of the heterotrimeric G protein G2 in Dictyostelium discoideum. Using cytoskeleton-free gradient-sensing cells, quantitative imaging, biochemical assays, FRET-based G-protein activation measurements, and structural modeling, we demonstrate that C2GAP1 controls concentration-dependent adaptation during gradient sensing. Mechanistically, C2GAP1 directly associates with G2 in both GDP- and GTP-bound states, with preferential binding to activated G2, thereby sustaining membrane recruitment and locally attenuating signaling. Loss of C2GAP1 enhances G-protein activation, disrupts front-specific inhibition, and impairs rapid reorientation in dynamic gradients. These findings define a direct coupling between heterotrimeric G proteins and a RasGAP as a core adaptive module that calibrates gradient sensing across wide concentration ranges. HighlightsChemotaxis, the directional migration of cells along chemoattractant gradients, underlies processes such as neuron patterning, lymphocyte recruitment, cancer metastasis, and Dictyostelium discoideum development. The hallmark of eukaryotic chemotaxis is the ability to sense and respond to gradients spanning wide concentration ranges through cellular adaptation. This process involves three interconnected modules: gradient sensing, cell polarity, and migration, with gradient sensing as the foundation. While many components of GPCR-mediated signaling are known, the molecular mechanisms driving adaptation remain unclear. Here, we show that the heterotrimeric G protein subunit interacts with RasGAP C2GAP1 to mediate adaptation during gradient sensing and chemotaxis.