Protein phosphatase 2A mediates resensitization of the neurokinin 1 receptor

Murphy, J. E.,, Roosterman, D., Cottrell, G. S. ORCID: https://orcid.org/0000-0001-9098-7627, 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 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.

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URI	https://reading-clone.eprints-hosting.org/id/eprint/30252
Item Type	Article
Refereed	Yes
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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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