Protein kinase C-mediated desensitization of the neurokinin 1 receptor

Olivier Déry, Kathryn A. Defea, Nigel W. Bunnett

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An understanding of the mechanisms that regulate signaling by the substance P (SP) or neurokinin 1 receptor (NK1-R) is of interest because of their role in inflammation and pain. By using activators and inhibitors of protein kinase C (PKC) and NK1-R mutations of potential PKC phosphorylation sites, we determined the role of PKC in desensitization of responses to SP. Activation of PKC abolished SP-induced Ca2+ mobilization in cells that express wild-type NK1-R. This did not occur in cells expressing a COOH-terminally truncated NK1-R (NK1-Rδ324), which may correspond to a naturally occurring variant, or a point mutant lacking eight potential PKC phosphorylation sites within the COOH tail (NK1-R Ser-338, Thr-339, Ser-352, Ser-387, Ser-388, Ser-390, Ser-392, Ser-394/Ala, NK1-RKC4). Compared with wild-type NK1-R, the t1/2 of SP-induced Ca2+ mobilization was seven- and twofold greater in cells expressing NK1-Rδ324 and NK1-RKC4, respectively. In cells expressing wild-type NK1-R, inhibition of PKC caused a 35% increase in the t1/2 of SP-induced Ca2+ mobilization. Neither inhibition of PKC nor receptor mutation affected desensitization of Ca2+ mobilization to repeated challenge with SP or SP-induced endocytosis of the NK1-R. Thus PKC regulates SP-induced Ca2+ mobilization by full-length NK1-R and does not regulate a naturally occurring truncated variant. PKC does not mediate desensitization to repeated stimulation or endocytosis of the NK1-R.

Original languageEnglish (US)
Pages (from-to)C1097-C1106
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5 49-5
StatePublished - 2001


  • Downregulation
  • G protein-coupled receptors
  • Substance P
  • Tachykinins

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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