Protons as second messenger regulators of G protein signaling

Daniel G. Isom, Vishwajith Sridharan, Rachael Baker, Sarah T. Clement, David M. Smalley, Henrik G. Dohlman

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)531-538
Number of pages8
JournalMolecular Cell
Issue number4
StatePublished - Aug 22 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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