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Recycling and resensitization of the neurokinin 1 receptor: influence of agonist concentration and Rab GTPases

Roosterman, D., Cottrell, G. S., Schmidlin, F., Steinhoff, M. and Bunnett, N. W. (2004) Recycling and resensitization of the neurokinin 1 receptor: influence of agonist concentration and Rab GTPases. The Journal of Biological Chemistry, 279 (29). pp. 30670-30679. ISSN 1083-351X

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To link to this item DOI: 10.1074/jbc.M402479200

Abstract/Summary

Substance P (SP) induces endocytosis and recycling of the neurokinin 1 receptor (NK1R) in endothelial cells and spinal neurons at sites of inflammation and pain, and it is thus important to understand the mechanism and function of receptor trafficking. We investigated how the SP concentration affects NK1R trafficking and determined the role of Rab GTPases in trafficking. NK1R trafficking was markedly influenced by the SP concentration. High SP (10 nM) induced translocation of the NK1R and beta-arrestin 1 to perinuclear sorting endosomes containing Rab5a, where NK1R remained for >60 min. Low SP (1 nM) induced translocation of the NK1R to early endosomes located immediately beneath the plasma membrane that also contained Rab5a and beta-arrestin 1, followed by rapid recycling of the NK1R. Overexpression of Rab5a promoted NK1R translocation to perinuclear sorting endosomes, whereas the GTP binding-deficient mutant Rab5aS34N caused retention of the NK1R in superficial early endosomes. NK1R translocated from superficial early endosomes to recycling endosomes containing Rab4a and Rab11a, and Rab11aS25N inhibited NK1R recycling. Rapid NK1R recycling coincided with resensitization of SP-induced Ca2+ mobilization and with the return of surface SP binding sites. Resensitization was minimally affected by inhibition of vacuolar H(+)-ATPase and phosphatases but was markedly suppressed by disruption of Rab4a and Rab11a. Thus, whereas beta-arrestins mediate NK1R endocytosis, Rab5a regulates translocation between early and sorting endosomes, and Rab4a and Rab11a regulate trafficking through recycling endosomes. We have thus identified a new function of Rab5a as a control protein for directing concentration-dependent trafficking of the NK1R into different intracellular compartments and obtained evidence that Rab4a and Rab11a contribute to G-protein-coupled receptor recycling from early endosomes.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30281
Uncontrolled Keywords:Animals Arrestins/chemistry/metabolism Blotting, Western Calcium/metabolism Cell Line DNA, Complementary/metabolism Dose-Response Relationship, Drug Endocytosis Endosomes/metabolism Flow Cytometry Glutathione Transferase/metabolism Green Fluorescent Proteins Kinetics Luminescent Proteins/metabolism Microscopy, Fluorescence Protein Structure, Tertiary Protein Transport Rats Receptors, G-Protein-Coupled/metabolism Receptors, Neurokinin-1/*chemistry/metabolism Temperature Time Factors rab GTP-Binding Proteins/*metabolism rab4 GTP-Binding Proteins/*metabolism rab5 GTP-Binding Proteins/metabolism
Additional Information:Roosterman, Dirk Cottrell, Graeme S Schmidlin, Fabien Steinhoff, Martin Bunnett, Nigel W DK39957/DK/NIDDK NIH HHS/ DK43207/DK/NIDDK NIH HHS/ J Biol Chem. 2004 Jul 16;279(29):30670-9. Epub 2004 May 5.
Publisher:American Society for Biochemistry and Molecular Biology

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