title: Heterologous regulation of trafficking and signaling of G protein-coupled receptors: beta-arrestin-dependent interactions between neurokinin receptors.
abstract: Cells express multiple G protein-coupled receptors that are simultaneously or sequentially activated by agonists. The consequences of activating one receptor on signaling and trafficking of another receptor are unknown. We examined the effects of selective activation of the neurokinin 1 receptor (NK1R) on signaling and trafficking of the NK3R and vice versa. Selective agonists of NK1R and NK3R induced membrane translocation of beta-arrestins (beta-ARRs). Dominant negative beta-ARR(319-418) inhibited endocytosis of NK1R and NK3R. Whereas an NK1R agonist caused sequestration of NK1R with beta-ARR in the same endosomes, thereby depleting them from the cytosol, beta-ARRs did not prominently sequester with the activated NK3R and rapidly returned to the cytosol. In cells coexpressing both receptors, prior activation of the NK1R inhibited endocytosis and homologous desensitization of the NK3R, which was dose-dependently reversed by overexpression of beta-ARR1. Similar results were obtained in enteric neurons that naturally coexpress the NK1R and NK3R. In contrast, activation of the NK3R did not affect NK1R endocytosis or desensitization. Thus, the high-affinity and prolonged interaction of the NK1R with beta-ARRs depletes beta-ARRs from the cytosol and limits their role in desensitization and endocytosis of the NK3R. Because beta-ARRs are critical for desensitization, endocytosis, and mitogenic signaling of many receptors, this sequestration is likely to have important and widespread implications.
authors.affiliation: Department of Surgery, University of California, 521 Parnassus Avenue, San Francisco, CA 94143-0660, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Schmidlin
authors.forename: Olivier
authors.initials: O
authors.lastname: Déry
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.forename: Eileen F
authors.initials: EF
authors.lastname: Grady
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D002461:Cell Line, Transformed; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D051379:Mice; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605255:Arrb1 protein, mouse; C000605256:Arrb1 protein, rat; D019390:Arrestins; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D019204:GTP-Binding Proteins