Protein kinase C-mediated desensitization of the neurokinin 1 receptor |
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Authors: | Déry O Defea K A Bunnett N W |
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Institution: | Departments of Surgery and Physiology, University of California San Francisco, San Francisco, California 94143-0660, USA. |
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Abstract: | An understanding of the mechanisms that regulate signaling bythe substance P (SP) or neurokinin 1 receptor (NK1-R) is of interestbecause of their role in inflammation and pain. By using activators andinhibitors of protein kinase C (PKC) and NK1-R mutations of potentialPKC phosphorylation sites, we determined the role of PKC indesensitization of responses to SP. Activation of PKC abolishedSP-induced Ca2+ mobilization in cells that expresswild-type NK1-R. This did not occur in cells expressing aCOOH-terminally truncated NK1-R (NK1-R 324), which may correspond toa naturally occurring variant, or a point mutant lacking eightpotential PKC phosphorylation sites within the COOH tail (NK1-RSer-338, Thr-339, Ser-352, Ser-387, Ser-388, Ser-390, Ser-392,Ser-394/Ala, NK1-RKC4). Compared with wild-type NK1-R, thet1/2 of SP-induced Ca2+mobilization was seven- and twofold greater in cells expressing NK1-R 324 and NK1-RKC4, respectively. In cells expressing wild-type NK1-R, inhibition of PKC caused a 35% increase in thet1/2 of SP-induced Ca2+mobilization. Neither inhibition of PKC nor receptor mutation affecteddesensitization of Ca2+ mobilization to repeated challengewith SP or SP-induced endocytosis of the NK1-R. Thus PKC regulatesSP-induced Ca2+ mobilization by full-length NK1-R and doesnot regulate a naturally occurring truncated variant. PKC doesnot mediate desensitization to repeated stimulation or endocytosis ofthe NK1-R. |
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