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Papers In Press, published online ahead of print July 17, 2006
J. Biol. Chem, 10.1074/jbc.M603369200
Submitted on April 7, 2006
Revised on June 21, 2006
Accepted on July 17, 2006

Ubiquitin-dependent down-regulation of the neurokinin-1 receptor

Graeme S. Cottrell, Benjamin Padilla, Stella Pikios, Dirk Roosterman, Martin Steinhoff, Daphne Gehringer, Eileen F. Grady, and Nigel W. Bunnett

Surgery and Physiology, UCSF, San Francisco, CA 94143-0660

Corresponding Author: nigel.bunnett{at}ucsf.edu

Transient stimulation with substance P (SP) induces endocytosis and recycling of the neurokinin-1 receptor (NK1R). The effects of sustained stimulation by high concentrations of SP on NK1R trafficking and Ca2+ signaling, as may occur during chronic inflammation and pain, are unknown. Chronic exposure to SP (100 nM, 3 h) completely desensitized Ca2+ signaling by NK1R wild type (NK1Rwt). Resensitization occurred after 16 h, and cycloheximide prevented resensitization, implicating new receptor synthesis. Lysine ubiquitination of G-protein coupled receptors is a signal for their trafficking and degradation. Lysine-deficient mutant receptors (NK1Rdelta 5K/R, C-terminal tail lysines; NK1Rdelta 10K/R, all intracellular lysines) were expressed at the plasma membrane and were functional because they responded to SP by endocytosis and by mobilization of Ca2+ ions. SP desensitized NK1Rwt, NK1Rdelta 5K/R and NK1Rdelta 10K/R. However, NK1Rdelta 5K/R and NK1Rdelta 10K/R resensitized 4 to 8-fold faster than NK1Rwt by cycloheximide-independent mechanisms. NK1Rdelta 325 (naturally occurring truncated variant) showed incomplete desensitization followed by a marked sensitization of signaling. By labeling receptors in living cells using antibodies to extracellular epitopes, we observed that SP induced endocytosis of NK1Rwt, NK1Rdelta 5K/R and NK1Rdelta 10K/R. After 4 h in SP-free medium, NK1Rdelta 5K/R and NK1Rdelta 10K/R recycled to the plasma membrane, whereas NK1Rwt remained internalized. SP induced ubiquitination of NK1Rwt and NK1Rdelta 5K/R, determined by immunoprecipitation under non-denaturing and denaturing conditions and detected with antibodies to mono- and poly-ubiquitin. NK1Rdelta 10K/R was not ubiquitinated. Whereas SP induced degradation of NK1Rwt, NK1Rdelta 5K/R and NK1Rdelta 10K/R showed ~50% diminished degradation. Thus, chronic stimulation with SP induces ubiquitination of the NK1R, which mediates its degradation and down-regulation.


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