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Trafficking of neurokinin receptors: regulation, mechanism and function
Author(s) -
Bunnett N.
Publication year - 2004
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/j.0906-6705.2004.00212s.x
Subject(s) - microbiology and biotechnology , endocytosis , receptor , endosome , clathrin , g protein coupled receptor , biology , immune receptor , cell surface receptor , internalization , signal transduction , chemistry , intracellular , biochemistry
Cellular responses to agonists of G‐protein‐coupled receptors (GPCRs) depend in large part on the trafficking of receptors between the plasma membrane and intracellular locations. Receptor activation usually triggers rapid endocytosis of receptors, which either recycle to the cell surface or are targeted for degradation, depending on the receptor in question and the nature of the stimulation. Activation of neurokinin receptors (NKRs) induces membrane translocation of G‐protein receptor kinases, which phosphorylate the receptors and β‐arrestins, which interact with phosphorylated receptors. β‐arrestins: 1) uncouple receptors from G‐proteins to mediate desensitization; 2) are adaptors for clathrin and AP‐2 and mediate clathrin and dynamin‐dependent endocytosis of receptors; and 3) interact with components of the MAP kinase pathway such as src, and thereby determine the subcellular location and function of activated MAP kinases. The fate of endocytosed NKRs depends on the receptor and the nature of the stimulus. Transient stimulation with low concentrations of SP (1 n m , 10 min) induces rapid recycling of the NK1R from superficially located endosomes by a mechanism that is mediated by rab4a and rab11a. Higher concentrations of SP (10 n m ) induce rab5a‐dependent trafficking of the NK1R to perinuclear sorting endosomes and a gradual recycling to the plasma membrane. Continuous stimulation with high concentrations of SP (100 n m , 180 min) induces NK1R ubiquitination and trafficking for degradation. The fate of endocytosed receptors also depends on their interaction with β‐arrestins. The NK1R forms stable high‐affinity interactions with both β‐arrestins 1 and 2 at the plasma membrane and in endosomes, whereas the NK3R interacts transiently only with β‐arrestin 2 at the cell surface. The nature of these interactions is specified by domains in the intracellular loop 3 and the carboxyl terminus and determine the rate of recycling and resensitization of these receptors.