PLCg2 Controls Neutrophil Sensitivity through Calcium Oscillation and Gates Chemoattractant Concentration Range for Chemotaxis

The connection between calcium oscillation and cell sensitivity is poorly understood. Calcium oscillation is triggered either spontaneously or upon receptor-ligand binding. The cytosolic [Ca2+] increase during calcium oscillation is initiated from Ca2+ release from the intracellular stores through the phospholipase C (PLC)-derived inositol 1,4,5-trisphosphate (IP3). Here, we show that neutrophils lacking PLC{gamma}2 (plcg2kd) display impaired spontaneous calcium oscillation and chemoattractant-induced calcium response, decreased membrane targeting of CAPRI (a RasGAP), and subsequent increased activations of Ras and its effectors, such as PI3K{gamma} activation and actin polymerization. More importantly, plcg2kd neutrophils sense and respond to chemoattractant at a subsensitive chemoattraction. Taken together, our results demonstrate that PLC{gamma}2 mediates spontaneous calcium oscillation, contributes to chemoattractant-triggered calcium response, controls neutrophil sensitivity through membrane targeting of CAPRI, and gates chemoattractant concentration range for neutrophil chemotaxis. HighlightsO_LINeutrophils lacking PLC{gamma}2 (plcg2kd) shows impaired spontaneous or GPCR-mediated Ca2+ oscillation. C_LIO_LIplcg2kd neutrophils display attenuated membrane targeting of CAPRI, a key negative regulator of Ras signaling and basal activity of neutrophils. C_LIO_LIplcg2kd neutrophils display an increased sensitivity and activation of GPCR-mediated signaling pathways. C_LIO_LIplcg2kd neutrophils display chemoattractant concentration-dependent alteration of chemotaxis behavior. C_LI