Endokinins

Peptide in a- / b-Tachykinin Precursor 4

A family of mammalian tachykinins with the carboxyl-terminal FXGLM-NH2 structure (X represents a hydrophobic amino acid residue) include three peptides: substance P (Code 4014-v), neurokinin A (Code 4154-v), and neurokinin B (Code 4317-v). They are involved in numerous groups have discovered the identical ligands to GPR7 and GPR8, which were designated either biological activities, such as muscle contraction, pain transmission through interacting with their specific receptors. Three mammalian tachykinin receptors, NK1, NK2, and NK3 are known to show the selectivity to substance P, neurokinin A, and neurokinin B, respectively. All of these tachykinin receptor ligands are encoded by several tachykinin precursor (TAC): substance P by aTAC1, neurokinin A by bTAC1 substance P/neurokinin A by gTAC1, and neurokinin B by TAC3. Very recently, new TACs, TAC4 and its splicing variants, have been cloned and the novel tachykinins, termed as endokinin A, B, C, and D, respectively, are reported[Proc. Natl. Acad. Sci. U.S.A., 100, 6245 (2003)].

The predicted primary structures of endokinin C and D share the common carboxyl-terminal FQGLL-NH2, while those of the corresponding endokinin A and B are FFGLM-NH2. Actually, the predicted structures of endokinin C and D are composed of the same 14 amino acid residues except for the amino-teminal 2 amino acids. Chemically synthesized endokinin C and D do not have affinity for human NK1 and NK2 receptors even at concentrations up to 10 mM. Similarly, they are very weak agonists to human NK3 receptor (Ki=56 and 28 mM, respectively). The activities thus far observed for synthetic endokinin C and D are: i) both peptides decrease mean arterial blood pressure dose-dependently at relatively higher doses between 10 and 100 nmol/kg; and ii) only endokinin C induces transient mesenteric vasoconstriction in rats. Considering the preservation of the common sequence motif of tachykinins with Met-to-Leu substitution, endokinin C and D may have the unidentified biological activities, with respect to the "fourth NK or related receptor", but this is not confirmed yet[Proc. Natl. Acad. Sci. U.S.A., 100, 6245 (2003)]. Thus, endokinin C and D may shed some light in clarifying the unsolved activities through the NK receptor near future.

Endokinin C: KKAYQLEHTFQGLL-NH2
Endokinin D: VGAYQLEHTFQGLL-NH2
Endokinin A/B: --GKASQFFGLM-NH2 (Common C-terminal sequence)