Histamine-induced biphasic activation of RhoA allows for persistent RhoA signaling

PLoS Biol. 2020 Sep 3;18(9):e3000866. doi: 10.1371/journal.pbio.3000866. eCollection 2020 Sep.


The small GTPase RhoA is a central signaling enzyme that is involved in various cellular processes such as cytoskeletal dynamics, transcription, and cell cycle progression. Many signal transduction pathways activate RhoA-for instance, Gαq-coupled Histamine 1 Receptor signaling via Gαq-dependent activation of RhoGEFs such as p63. Although multiple upstream regulators of RhoA have been identified, the temporal regulation of RhoA and the coordination of different upstream components in its regulation have not been well characterized. In this study, live-cell measurement of RhoA activation revealed a biphasic increase of RhoA activity upon histamine stimulation. We showed that the first and second phase of RhoA activity are dependent on p63 and Ca2+/PKC, respectively, and further identified phosphorylation of serine 240 on p115 RhoGEF by PKC to be the mechanistic link between PKC and RhoA. Combined approaches of computational modeling and quantitative measurement revealed that the second phase of RhoA activation is insensitive to rapid turning off of the receptor and is required for maintaining RhoA-mediated transcription after the termination of the receptor signaling. Thus, two divergent pathways enable both rapid activation and persistent signaling in receptor-mediated RhoA signaling via intricate temporal regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium Signaling / drug effects
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • HeLa Cells
  • Histamine / pharmacology*
  • Humans
  • Mice
  • Phosphorylation / drug effects
  • Protein Kinase C / metabolism
  • Receptors, Histamine / metabolism
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Signal Transduction / drug effects
  • rhoA GTP-Binding Protein / metabolism*


  • Receptors, Histamine
  • Rho Guanine Nucleotide Exchange Factors
  • RHOA protein, human
  • Histamine
  • Protein Kinase C
  • rhoA GTP-Binding Protein