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Mol Cell. 2013 Aug 22;51(4):531-8. doi: 10.1016/j.molcel.2013.07.012. Epub 2013 Aug 15.

Protons as second messenger regulators of G protein signaling.

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  • 1Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.


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.

Copyright © 2013 Elsevier Inc. All rights reserved.

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