Novel Pharmacology of Substance K-Binding Sites: a Third Type of Tachykinin Receptor

Abstract

The tachykinins are a family of peptides with the carboxyl terminal amino acid sequence Phe-X-Gly-Leu-Met-NH2. Three major mammalian tachykinins have been identified--substance K, neuromedin K, and substance P--but only two tachykinin receptors have been postulated. Three tachykinins were labeled with radioiodinated Bolton-Hunter reagent and their binding characteristics were determined in crude membrane suspensions from several tissues. In cerebral cortex labeled eledoisin exhibited high-affinity binding that was inhibited by tachykinins in a manner indicating a definitive SP-E receptor site. In gastrointestinal smooth muscle and bladder, high-affinity binding of labeled substance P was inhibited in a pattern indicating a definitive SP-P site. In intestinal smooth muscle and bladder, however, labeled substance K and labeled eledoisin were both bound in a pattern indicating a preference for substance K itself. The results suggest the existence of three distinct types of tachykinin receptors: SP-P, SP-E, and SP-K.

Modulation of the immune response by tachykinins

“…Interest in multiple NK receptors has arisen from studies showing that peripheral tissues contain predominantly NK-1 and NK-2 receptors (13)(14)(15). In the immune system, there has not been a systematic investigation of TK-receptor type specificities, although NK receptors are known to exist both in lymphoid tissues and on lymphocytes.…”

Tachykinin antagonist. I: Specific, competitive and tissue-selective neurokinin B antagonists on contractile activity in smooth muscles.

“…

[3][4][5][6][7][8][9][10], were tested for agonistic activity as well as for their ability to antagonize the myotropic actions of NKB, neurokinin A, substance P, physalaemin and eledoisin in isolated guinea-pig ileum, guinea-pig urinary bladder, rat duode num, rat vas deferens and rat portal vein.[GIy6]-NKB [3][4][5][6][7][8][9][10] in the guinea-pig ileum and rat portal vein and [Arg3, D-Ala6]-NKB [3][4][5][6][7][8][9][10] in the guinea-pig ileum were found to be the first specific and competitive antagonists against NKB.

…”

“…Our study (3) on NKB [3][4][5][6][7][8][9][10] [H-His-Asp Phe-Phe-Val-Gly-Leu-Met-NH2] suggests that the amino acid residues at positions 4, 5, 6 and 7 of the NKB molecule may be respon sible for tachykinin receptors, which have been subdivided into SP-P, SP-E and SP-K types in the smooth muscles of mammals by Buck et al (4), Lee et al (5) and Laufer et al (6). Furthermore, NKB related octapeptides analogs, [GIy6]-NKB [3][4][5][6][7][8][9][10] [H-His-Asp Phe-Gly-Val-Gly-Leu- Met-NH2] and [Arg3, D-Ala6]-NKB [3][4][5][6][7][8][9][10] [H-Arg-Asp-Phe-D Ala-Val-Gly-Leu-Met NH2], were found to be fairly potent antagonists against NKB in the isolated guinea-pig ileum, but not against substance P and neurokinin A (7).…”

“…Furthermore, NKB related octapeptides analogs, [GIy6]-NKB [3][4][5][6][7][8][9][10] [H-His-Asp Phe-Gly-Val-Gly-Leu- Met-NH2] and [Arg3, D-Ala6]-NKB [3][4][5][6][7][8][9][10] [H-Arg-Asp-Phe-D Ala-Val-Gly-Leu-Met NH2], were found to be fairly potent antagonists against NKB in the isolated guinea-pig ileum, but not against substance P and neurokinin A (7).…”

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

“…NKB interacts with all three mammalian GPCR tachykinin receptors (TACR1, TACR2 and TACR3) but has highest selectivity for TACR3. This NKB selective tachykinin receptor was first identified through binding studies in mammalian CNS and functional studies using guinea pig illeum [140][141][142] , leading to the cloning of the human TACR3 in 1992 143 .…”