Protons as Second Messenger Regulators of G Protein Signaling

• Published in: Molecular cell Vol. 51; no. 4; pp. 531 - 538
• Main Authors: Isom, Daniel G., Sridharan, Vishwajith, Baker, Rachael, Clement, Sarah T., Smalley, David M., Dohlman, Henrik G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.08.2013
• Subjects: Algorithms; computers; G-protein coupled receptors; gene expression; GTP-Binding Protein alpha Subunits - chemistry; GTP-Binding Protein alpha Subunits - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Hydrogen-Ion Concentration; Phosphorylation; Protein Binding; Protein Structure, Tertiary; proteins; Protons; Receptors, G-Protein-Coupled - metabolism; Second Messenger Systems; Signal Transduction; stress response; Stress, Physiological; Temperature
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2013.07.012

In response to environmental stress, cells often generate pH signals that serve to protect vital cellular components and reprogram gene expression for survival. A major barrier to our understanding of this process has been the identification of signaling proteins that detect changes in intracellular pH. To identify candidate pH sensors, we developed a computer algorithm that searches proteins for networks of proton-binding sidechains. This analysis indicates that Gα subunits, the principal transducers of G protein-coupled receptor (GPCR) signals, are pH sensors. Our structure-based calculations and biophysical investigations reveal that Gα subunits contain networks of pH-sensing sidechains buried between their Ras and helical domains. Further, we show that proton binding induces changes in conformation that promote Gα phosphorylation and suppress receptor-initiated signaling. Together, our computational, biophysical, and cellular analyses reveal an unexpected function for G proteins as mediators of stress-response signaling. •Cellular pH is altered by nutritional and metabolic stress•A structure-based algorithm predicts pH sensing by Gα proteins•Proton binding alters Gα conformation, phosphorylation, and signal transmission•G proteins serve as integrators of receptor- and stress-mediated cell signaling