Neuropeptide Y (NPY), Analogs and Fragments

Definition
Neuromedins, smooth-muscle-stimulating peptides, are commonly divided into four groups: bombesin-like, kassinin-like, neurotensin-like and neuromedins U. These neuropeptides and their receptors are localized to all components of the HPA axis, the only exemption seems to be neurokinin B, which is not detected in the adenohypophysis 1.

Related Peptides
Nine neuromedins (B, B-30, B-32, C, K, L, N, U-8 and U-25) thus far identified in porcine spinal cord as the smooth-muscle stimulating peptides, are classified into four families; B-(bombesin-like), K-(kassinine-like), N-(neurotensin-like) and U-groups 2.

Discovery
Minamino et al., identified Neuromedin B, K, L, C, B-32, B-30, U-8, U-25, in porcine spinal cord, between 1983 and 1985 3. In 2008, Mori et al., isolated Neuromedin S, a novel neuropeptide of 36 amino acids, from rat brain as an endogenous ligand for the orphan G protein-coupled receptors FM-3/GPR66 and FM-4/TGR-1, identified to date as type-1 and type-2 neuromedin U (NMU) receptors, respectively. The peptide was designated neuromedin S (NMS) because it is specifically expressed in the suprachiasmatic nucleus of the hypothalamus 4.

Structural characteristics
Porcine neuromedin K has been identified by microsequencing as: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH24. The sequence thus determined has been confirmed by synthesis. Neuromedin K has been found to have not only a remarkable sequence homology to kassinin and substance P, but also a prompt stimulant activity on guinea-pig ileum in a manner similar to that of substance P, suggesting that neuromedin K may be involved in neural transmission 6.

Novel mammalian tachykinin, designated "neuromedin L", has been isolated from porcine spinal cord by using bioassay for a tachykinin-like effect on contractility of smooth muscle preparation from guinea pig ileum. By microsequencing, the peptide has been determined to be His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2. This structure has been confirmed by synthesis. Neuromedin L is found to elicit a prompt stimulant activity on guinea pig ileum in a manner similar to that of substance P, and to have remarkable sequence homology to kassinin as well as neuromedin K, which was earlier identified as a mammalian tachykinin. These facts suggest that neuromedin L may participate in neural transmission in the same manner as other members of the mammalian tachykinin family, such as substance P and neuromedin K 7.

Sequence analyses and syntheses revealed that neuromedin U-8 is a novel octapeptide with a C-terminal amide structure, while U-25 contains the U-8 sequence at its C-terminus, preceded by paired Arg residues, implicating their biosynthetic relationship. Their potent uterus stimulating activity and hypertensive effect, as well as their unique C-terminal amide structure are indicative of their specialized physiological function 5.

Neuromedin C was obtained from a side fraction of neuromedin B. It is another decapeptide that exhibits a potent stimulant effect on the smooth muscle preparation of rat uterus. By microsequencing and synthesis, the amino acid sequence of the peptide has been identified as: Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2. This peptide is found to be identical with the carboxy-terminal subsequence [18-27] of gastrin releasing peptide, and to display a potent contractile activity on rat uterus in the characteristic manner of bombesin. These facts strongly suggest that the peptide may be a neuromediator in the neural communication systems of mammals 8.

Neuromedin S is structurally related to Neuromedin U. These peptides share a C-terminal core structure4.

Mode of Action
Two structurally related, G-protein-coupled receptors, FM-3 and FM-4, are specific and functional receptors for neuromedin U, designated NMU1 and NMU2, respectively. NMU1 is expressed predominantly in peripheral tissues, whereas NMU2 is more highly expressed in the central nervous system 9. Functional screening assays suggest that NmU-R1 and NmU-R2 of human and rodent origin are able to mediate intracellular Ca2+ signaling with potency in the nanomolar range. Activation of either hNmU-R1 or hNmU-R2 is also able to stimulate the release of arachidonic acid, most likely through a Ca2+-dependent activation of phospholipase A2 10. The receptor that interacts with the mammalian bombesin-related peptide neuromedin B (NMB) is ubiquitous in the gastrointestinal tract and central nervous system. Activation of the receptor for NMB stimulates phospholipase C and increases intracellular Ca2+ 11.

Functions
Neuromedins exert a manifold effect on HPA axis, and their action on the adrenal suggests their involvement in the regulation of growth, structure and function of the adrenal cortex. Neuromedins may exert both direct and indirect effects on the adrenal cortex. Direct effect is proven by the stimulation of mineralo- and glucocorticoid output by isolated or cultured adrenocortical cells and by mobilisation of intracellular [Ca2+]i. Indirect effects, on the other hand, may be mediated by ACTH, arginine-vasopressin, angiotensin II, catecholamines or by other regulatory substances of medullary origin 1.

References
1.Malendowicz LK (1998). Role of neuromedins in the regulation of adrenocortical function. Horm Metab Res., 30(6-7):374-383.
2.Minamino N, Sudoh T, Kangawa K, Matsuo H (1985). Neuromedins: novel smooth-muscle stimulating peptides identified in porcine spinal cord. Peptides, 6(3):245-248.
3.Minamino N, Kangawa K, Matsuo H (1983). Neuromedin B: a novel bombesin-like peptide identified in porcine spinal cord. Biochem Biophys Res Commun., 114(2):541-548.
4.Mori K, Miyazato M, Kangawa K (2008). Neuromedin S: discovery and functions. Results Probl Cell Differ.,46:201-212.
5.Minamino N, Sudoh T, Kangawa K, Matsuo H (1985). Neuromedins: novel smooth-muscle stimulating peptides identified in porcine spinal cord. Peptides, 6(3):245-248.
6.Kangawa K, Minamino N, Fukuda A, Matsuo H (1983). Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord. Biochem Biophys Res Commun., 114(2):533-540.
7.Minamino N, Kangawa K, Fukuda A, Matsuo H (1984). Neuromedin L: a novel mammalian tachykinin identified in porcine spinal cord. Neuropeptides, 4(2):157-166.
8.Minamino N, Kangawa K, Matsuo H (1984). Neuromedin C: a bombesin-like peptide identified in porcine spinal cord. Biochem Biophys Res Commun., 119(1):14-20.
9.Raddatz R, Wilson AE, Artymyshyn R, Bonini JA, Borowsky B, Boteju LW, Zhou S, Kouranova EV, Nagorny R, Guevarra MS, Dai M, Lerman GS, Vaysse PJ, Branchek TA, Gerald C, Forray C, Adham N (2000). Identification and Characterization of Two Neuromedin U Receptors Differentially Expressed in Peripheral Tissues and the Central Nervous System. J. Biol. Chem., 275(42):32452-32459.
10. Paul J. Brighton, Philip G. Szekeres and Gary B. Willars (2004). Neuromedin U and Its Receptors: Structure, Function, and Physiological Roles. Pharmacol Rev., 56:231-248.
11. Benya RV, Wada E, Battey JF, Fathi Z, Wang LH, Mantey SA, Coy DH, Jensen RT(1997). Neuromedin B receptors retain functional expression when transfected into BALB 3T3 fibroblasts: analysis of binding, kinetics, stoichiometry, modulation by guanine nucleotide-binding proteins, and signal transduction and comparison with natively expressed receptors. Mol Pharmacol., 42(6):1058-1068.