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Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor

Murphy, J. E.,, Roosterman, D., Cottrell, G. S., Padilla, B. E., Feld, M., Brand, E., Cedron, W. J., Bunnett, N. W. and Steinhoff, M. (2011) Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor. American Journal of Physiology. Cell Physiology, 301 (4). C780-C791. ISSN 1522-1563

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To link to this item DOI: 10.1152/ajpcell.00096.2011

Abstract/Summary

Activated G protein-coupled receptors (GPCRs) are phosphorylated and interact with beta-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(1)R). Herein, we report a novel mechanism of resensitization by which protein phosphatase 2A (PP2A) is recruited to dephosphorylate noninternalized NK(1)R. 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(1)R. SP induced association of beta-arrestin1 and PP2A with noninternalized NK(1)R. beta-Arrestin1 small interfering RNA knockdown prevented SP-induced association of cell-surface NK(1)R with PP2A, indicating that beta-arrestin1 mediates this interaction. ECE-1 inhibition, by trapping beta-arrestin1 in endosomes, also impeded SP-induced association of cell-surface NK(1)R with PP2A. Resensitization of NK(1)R signaling required both PP2A and ECE-1 activity. Thus, after stimulation with SP, PP2A interacts with noninternalized NK(1)R and mediates resensitization. PP2A interaction with NK(1)R requires beta-arrestin1. ECE-1 promotes this process by releasing beta-arrestin1 from NK(1)R in endosomes. These findings represent a novel mechanism of PP2A- and ECE-1-dependent resensitization of GPCRs.

Item Type:Article
Refereed:Yes
Divisions:No Reading authors. Back catalogue items
ID Code:30252
Uncontrolled Keywords:Bacteriocins Cell Membrane/*physiology Gene Expression Regulation/*physiology Humans Indoles/pharmacology Maleimides/pharmacology Peptides Protein Isoforms Protein Kinase C/antagonists & inhibitors Protein Phosphatase 2/genetics/*metabolism Receptors, G-Protein-Coupled Receptors, Neurokinin-1/genetics/*metabolism Signal Transduction
Additional Information:Full text available either via DOI or PUBMED.
Publisher:American Physiological Society

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