Editors' ChoicePain

Neuropeptide-Mediated Receptor Trafficking

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Science's STKE  30 Aug 2005:
Vol. 2005, Issue 299, pp. tw313
DOI: 10.1126/stke.2992005tw313

Guan et al. have provided an intriguing link between pain pathways and pathways that mediate analgesia by demonstrating that protachykinin--the precursor to the pain-promoting neuropeptide substance P--regulates insertion of the δ-opioid receptor (DOR) into the plasma membrane. Opioid receptors on pain-sensing neurons mediate the inhibitory effects of opiates on pain. Whereas the μ-opioid receptor is constitutively transported to the membrane, DOR, which is sorted into the large dense-core vesicles (LDCV) that store secreted neuropeptides, is inserted into the membrane in response to DOR agonists or neuronal firing. Guan et al. noted that, in dorsal root ganglion (DRG) neurons containing substance P, DORs colocalized with substance P in LDCV. In mice lacking the preprotachykinin A gene (PPT-A, which encodes substance P and other tachykinin peptides), DORs were not associated with LDCVs. By expressing different portions of a substance P precursor in HEK293 cells induced to express LDCV-like vesicles, the authors determined that the DOR sorting signal was in the substance P domain. They combined coimmunoprecipitation, domain swapping, mutational analysis, and immunocytochemistry to show that the third luminal (extracellular, in the plasma membrane) domain of DOR interacted with the substance P domain of protachykinin and that DOR sorting to LDCV depended on this interaction. Stimulus-dependent membrane insertion of DOR was attenuated in PPT-A knockout mice, and DOR abundance was reduced in laminae I and II of the dorsal horn of the spinal cord. Moreover, both DOR-mediated spinal analgesia and morphine tolerance were eliminated. Thus, the pronociceptive peptide substance P is responsible for DOR sorting into LDCV and therefore its regulated insertion into the plasma membrane. Julius and Basbaum discuss the implications of this research.

J.-S. Guan, Z.-Z. Xu, H. Gao, S.-Q. He, G.-Q. Ma, T. Sun, L.-H. Wang, Z.-N. Zhang, I. Lena, I. Kitchen, R. Elde, A. Zimmer, C. He, G. Pei, L. Bao, X. Zhang, Interaction with vesicle luminal protachykinin regulates surface expression of δ-opioid receptors and opioid analgesia. Cell 122, 619-631 (2005). [Online Journal]

D. Julius, A. Basbaum, A neuropeptide courier for δ-Opioid receptors? Cell 122, 496-498 (2005). [Online Journal]

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