The role of the amino-terminal domain of tachykinins in neurokinin-1 receptor signaling and desensitization.
Neurokinin A (NKA) has previously been shown to be a full agonist of the neurokinin-1 receptor (NK-1R) but is only able to cause partial homologous desensitization of the receptor compared to substance P (SP). NKA and SP share the same amino acid sequence at their C-terminal active site domains but differ in structure at their N-terminal domains. These observations have led to the proposal that the N-terminal domains of tachykinin peptides affect the desensitization but not the agonist activities of the peptides. Some of the preprotachykinin proteins contain SP and the NKA-like tachykinins neuropeptide K (NPK) and neuropeptide gamma (NPgamma), which contain NKA at their C-terminals and are N-terminally extended. In this study, the abilities of NKA, NPK, and NPgamma to stimulate NK-1R second messenger (IP(3)) signaling and rapid homologous desensitization of the NK-1R were examined. In addition, a similar analysis was performed using several nonmammalian tachykinin peptides in order to obtain additional insight into the role of the tachykinin N-terminal domain in these NK-1R functions. NPK and NPgamma were found, like NKA, to be full agonists of rat NK-1R IP(3) signaling but, unlike NKA, were also able to cause full rapid homologous desensitization of the receptor. The extended N-terminal domains of NPK and NPgamma thus increase the desensitization activities of these NKA-like peptides. Of the nonmammalian tachykinins tested, all were full agonists but kassinin and eledoisin had only partial homologous desensitization activity, suggesting that the N-terminal structures of these peptides also differentially affect agonist versus desensitization activities of the NK-1R.
Vigna
Steven R
SR
Department of Cell Biology, Box 3709, Duke University Medical Center, Durham V.A. Medical Center, Durham, NC 27710, USA. srv@duke.edu
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D007293:Inosine Triphosphate / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D064729:Neurokinin-1 Receptor Antagonists; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000187:drug effects*; D015290:Second Messenger Systems / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D015320:Tachykinins / Q000494:pharmacology*; D014162:Transfection
D018076:DNA, Complementary; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D015320:Tachykinins; D007293:Inosine Triphosphate