FIGURE 7.

The regulation and NK₁R signaling and trafficking. 1: The cell-surface peptidase neprilysin (NEP) degrades and inactivates SP in the extracellular fluid and thereby limits NK₁R activation. 2: The SP-occupied NK₁R is a substrate for GRK 2, 3, and 5, which phosphorylate Ser and Thr residues in intracellular loop 3 and the COOH-terminal tail. Phosphorylation increases affinity of the NK₁R for β-arrestins (βarrs), which translocate to the plasma membrane, interact with the NK₁R, and mediate G protein uncoupling and receptor desensitization. β-Arrestins also recruit protein phosphate 2A (PP2A), which can dephosphorylate and thereby resensitize the cell-surface receptor. 3: β-Arrestins are adaptor proteins for clathrin and AP2 and thereby promote dynamin-dependent endocytosis of the SP and the NK₁R. 4: By recruiting the NK₁R together with Src, MEKK, and ERK1/2 to endosomes, β-arrestins assemble signalosomes that allow the endocytosed NK₁R to continue to signal. Rab5a mediates trafficking to early endosomes. 5: The NK₁R can rapidly recycle from superficially located endosomes by rab4a- and rab11a-dependent mechanisms. 6: Alternatively, the NK₁R traffics to endosomes in a perinuclear location that contain ECE-1. ECE-1 degrades SP in acidified endosomes and thereby destabilizes the SP/NK₁R/β-arrestin/Src/MEKK and ERK1/2 signaling complex. 7: The NK₁R then slowly recycles, which also mediate resensitization (8). 9: After sustained stimulation with high concentrations of SP, the NK₁R is ubiquitinated and traffics to lysosomes, where degradation downregulates SP signaling.