title: Analysis of C-terminally substituted tachykinin-like peptide agonists by means of aequorin-based luminescent assays for human and insect neurokinin receptors.
abstract: Aequorin-based assays for stable fly, Stomoxys calcitrans, (STKR) and human (neurokinin receptor 1 (NK1), neurokinin receptor 2 (NK2)) neurokinin-like receptors were employed to investigate the impact of a C-terminal amino acid exchange in synthetic vertebrate ('FXGLMa') and invertebrate ('FX1GX2Ra') tachykinin-like peptides. C-terminally (Arg to Met) substituted analogs of the insect tachykinin-related peptide, Lom-TK I, displayed increased agonistic potencies in luminescent assays for human NK1 and NK2 receptors, whereas they showed reduced potencies in the STKR-assay. The opposite effects were observed when C-terminally (Met to Arg) substituted analogs of substance P were analysed. These substance P analogs proved to be very potent STKR-agonists, being more potent than Lom-TK I. On the other hand, Lom-TK-LMa, was shown to be a very potent NK1-agonist and was suggested to have more substance-P-mimetic than neurokinin-A-mimetic properties. NK1 and NK2 receptor agonists appeared to be more sensitive to changes at the penultimate amino acid position than STKR-agonists. This is also reflected in the sequence conservation that is observed in the naturally occurring tachykinin subgroups ('FXGLMa' vs. 'FX1GX2Ra'). The differential Arg-Met preference appears to be a major coevolutionary change between insect and human peptide-receptor couples. With regard to the peptide agonists, this change can theoretically be based on a single point mutation.
authors: Laboratory for Developmental Physiology and Molecular Biology, Zoological Institute K.U.Leuven, Naamsestraat 59, B-3000, Leuven, Belgium.
authors: Herbert
authors: H
authors: Torfs
authors: Michel
authors: M
authors: Detheux
authors: Hendrica B
authors: HB
authors: Oonk
authors: Karl E
authors: KE
authors: Akerman
authors: Jeroen
authors: J
authors: Poels
authors: Tom
authors: T
authors: Van Loy
authors: Arnold
authors: A
authors: De Loof
authors: Gilbert
authors: G
authors: Vassart
authors: Marc
authors: M
authors: Parmentier
authors: Jozef
authors: J
authors: Vanden Broeck
mesh_terms: D000331:Aequorin / Q000737:chemistry*; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine / Q000235:genetics; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006801:Humans; D007313:Insecta; D008715:Methionine / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000819:agonists* / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000819:agonists* / Q000378:metabolism; D013045:Species Specificity; D013373:Substance P / Q000494:pharmacology; D015320:Tachykinins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; D013373:Substance P; D000331:Aequorin; D001120:Arginine; D008715:Methionine