Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor

Jane E. Murphy, Dirk Roosterman, Graeme S. Cottrell, Benjamin E. Padilla, Micha Feld, Eva Brand, Wendy J. Cedron, Nigel W. Bunnett, Martin Steinhoff

Research output: Contribution to journalArticlepeer-review


Activated G protein-coupled receptors (GPCRs) are phosphorylated and interact with β-arrestins, which mediate desensitization and endocytosis. Endothelin-converting enzyme-1 (ECE-1) degrades neuropeptides in endosomes and can promote recycling. Although endocytosis, dephosphorylation, and recycling are accepted mechanisms of receptor resensitization, a large proportion of desensitized receptors can remain at the cell surface. We investigated whether reactivation of noninternalized, desensitized (phosphorylated) receptors mediates resensitization of the substance P (SP) neurokinin 1 receptor (NK 1R). Herein, we report a novel mechanism of resensitization by which protein phosphatase 2A (PP2A) is recruited to dephosphorylate noninternalized NK 1R. A desensitizing concentration of SP reduced cell-surface SP binding sites by only 25%, and SP-induced Ca 2+ signals were fully resensitized before cell-surface binding sites started to recover, suggesting resensitization of cell-surface-retained NK 1R. SP induced association of β-arrestin1 and PP2A with noninternalized NK 1R. β-Arrestin1 small interfering RNA knockdown prevented SP-induced association of cell-surface NK 1R with PP2A, indicating that β-arrestin1 mediates this interaction. ECE-1 inhibition, by trapping β-arrestin1 in endosomes, also impeded SP-induced association of cell-surface NK 1R with PP2A. Resensitization of NK 1R signaling required both PP2A and ECE-1 activity. Thus, after stimulation with SP, PP2A interacts with noninternalized NK 1R and mediates resensitization. PP2A interaction with NK 1R requires β-arrestin1. ECE-1 promotes this process by releasing β-arrestin1 from NK 1R in endosomes. These findings represent a novel mechanism of PP2A-and ECE-1-dependent resensitization of GPCRs.

Original languageEnglish (US)
Pages (from-to)C780-C791
JournalAmerican Journal of Physiology - Cell Physiology
Issue number4
StatePublished - Oct 2011


  • Endothelinconverting enzyme-1
  • G protein-coupled receptor
  • Neuropeptide
  • Substance P
  • β-arrestins

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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