Neurokinin 1 receptors regulate morphine-induced endocytosis and desensitization of mu-opioid receptors in CNS neurons.
mu-Opioid receptors (MORs) are G-protein-coupled receptors (GPCRs) that mediate the physiological effects of endogenous opioid neuropeptides and opiate drugs such as morphine. MORs are coexpressed with neurokinin 1 receptors (NK1Rs) in several regions of the CNS that control opioid dependence and reward. NK1R activation affects opioid reward specifically, however, and the cellular basis for this specificity is unknown. We found that ligand-induced activation of NK1Rs produces a cell-autonomous and nonreciprocal inhibition of MOR endocytosis induced by diverse opioids. Studies using epitope-tagged receptors expressed in cultured striatal neurons and a neuroblastoma cell model indicated that this heterologous regulation is mediated by NK1R-dependent sequestration of arrestins on endosome membranes. First, endocytic inhibition mediated by wild-type NK1Rs was overcome in cells overexpressing beta-arrestin2, a major arrestin isoform expressed in striatum. Second, NK1R activation promoted sequestration of beta-arrestin2 on endosomes, whereas MOR activation did not. Third, heterologous inhibition of MOR endocytosis was prevented by mutational disruption of beta-arrestin2 sequestration by NK1Rs. NK1R-mediated regulation of MOR trafficking was associated with reduced opioid-induced desensitization of adenylyl cyclase signaling in striatal neurons. Furthermore, heterologous regulation of MOR trafficking was observed in both amygdala and locus ceruleus neurons that naturally coexpress these receptors. These results identify a cell-autonomous mechanism that may underlie the highly specific effects of NK1R on opioid signaling and suggest, more generally, that receptor-specific trafficking of arrestins may represent a fundamental mechanism for coordinating distinct GPCR-mediated signals at the level of individual CNS neurons.
Yu
Y Joy
YJ
Program in Neuroscience, University of California at San Francisco, San Francisco, California 94158-2140, USA.
Arttamangkul
Seksiri
S
Evans
Christopher J
CJ
Williams
John T
JT
von Zastrow
Mark
M
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019921:Biotinylation / Q000379:methods; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000166:cytology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D005260:Female; D008125:Locus Coeruleus / Q000166:cytology; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology; D014162:Transfection / Q000379:methods
D000701:Analgesics, Opioid; D018040:Receptors, Neurokinin-1; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013373:Substance P; D004744:Enkephalin, Methionine; D009020:Morphine; D000242:Cyclic AMP