ABSTRACT Understanding proton-gating (H+-gating) of GPCR activity is a major new frontier in signaling biology. GPCRs regularly encounter coincident H+ signals in various contexts, such as endosomes, tumors, synapses, inflamed tissue, and immune responses. However, the extent to which these signals regulate GPCR function represents a significant gap in our understanding of cellular sensing, communication, and drug discovery. Our research program aims to provide this insight for much of the GPCRome. Recently, using in vitro cell models and mass spectrometry, we discovered that changes in extracellular pH rapidly alter the lipid composition of cell membranes. Because lipids are critical regulators of GPCR activity, this unexpected finding led us to question whether coincident pH signals can (in)directly modulate GPCR function by rapidly altering the membrane lipid composition. Our preliminary studies indicate this hypothesis is correct, which has motivated our developing lipidomics as a new and unanticipated branch of our R35 research program. To this end, we have acquired an Agilent mass spectrometer, but we lack a proper instrument for extracting cellular lipidomes without oxidizing or degrading the lipids we seek to quantify. We are requesting support for a ThermoFisher SPD140P1 speed vacuum concentrator to solve this problem. The capability of the SPD140P1 would help us greatly accelerate our understanding of lipid- GPCR interactions and the ability of coincident acid signals to alter cell membranes (e.g., their composition, thickness, and curvature) to modulate GPCR function. As such, NIGMS support for our instrument request would help to catalyze a substantial leap forward in the GPCR field and beyond.