Neuromedin

The group of peptides known as tachykinins include substance P, substance K or neurokinin A, and neuromedin K, ie, neurokinin B, as well as a number of nonmammalian peptides. All members of this family contain the conserved carboxy-terrninal sequence Phe-X-Gly-Leu-Met-NH2, where X is an aromatic, ie, Phe or Tyr, or branched aliphatic, eg, Val or lie, amino acid. In general, this C-terminal sequence is cmcial for tachykinin activity (33) in fact, both the methionineamide and the C-terminal amide are cmcial for activity. The nature of the X residue in this sequence determines pharmacological identity (34,35) thus the substance P group contains an aromatic residue in this position, while the substance K group contains an aliphatic residue (33). 

Biosynthesis. Two closely related genes encode the three mammalian tachykinins. The preprotachykinin A gene encodes both substance P and substance K, while the preprotachykinin B gene encodes neuromedin K (45—47). The active sequences are flanked by the usual double-basic amino acid residues, and the carboxy-terrninal amino acid is a glycine residue which is decarboxylated to an amide. As with most neuropeptide precursors, intermediates in peptide processing can be detected, but their biological activities are not clear (ca 1994). 

GPR66 (TGR1, FM3) Neuromedin U Regional vasoconstriction, inotropy... 

Neuromedin U is a neuropeptide which is widely distributed in the gut and central nervous system. Peripheral activities of neuromedin U include stimulation of smooth muscle, increase in blood pressure, alteration of ion transport in the gut, control of local blood flow and regulation of adrenocortical function. The actions of neuromedin U are mediated by G-protein coupled receptors (NMU1, NMU2) which are coupled tO Gq/11. 

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

Neurotensin/Neuromedin N. Table 1 Structures and and potential therapeutical uses of NT receptor ligands... 

Neurotensin/Neuromedin N. Table 2 NTS1 and NTS2 signaling properties... 

Tachykinin NK2 receptor TK NK2r Neurokinin-2 receptor, neurokinin A receptor, substance K receptor, neurokinin-alpha receptor, Neuromedin L receptor... 

Tachykinin NK3 receptor TK NK3r Neurokinin-3 receptor, neurokinin B receptor, neurokinin-beta receptor, Neuromedin K receptor... 

Semi-rational approaches Four subt)rpes of the bombesin receptor have been identified (gastrin-releasing peptide [GRP] receptor, neuromedin B receptor, the orphan receptor bombesin receptor subtype 3 and bombesin receptor subtype 4). The roles of individual receptor... 

GPR39 Brain-gut peptides Neuromedin U receptors ligands... 

Neurotensin (NT) is a tridecapeptide that was first isolated from the central nervous system but subsequently was found to be present in the gastrointestinal tract and in the circulation. It is synthesized as part of a larger precursor that also contains neuromedin N, a six-amino-acid NT-like peptide. 

In the brain, processing of the precursor leads primarily to the formation of NT and neuromedin N these are released together from nerve endings. In the gut, processing leads mainly to the formation of NT and a larger peptide that contains the neuromedin N sequence at the carboxyl terminal. Both peptides are secreted into the circulation after ingestion of food. Most of the activity of NT is mediated by the last six amino acids, NT(8-13). 

GRP 119) 53 was isolated from porcine mucosae and causes gastrin secretion. The C-terminal decapeptide of GRP is, with the exception of His20, identical with that of bombesin 54, and also coincides with the sequence of the decapeptide neuromedin C 119b,c) [Gly18-Met27]-GRP. Neuromedin C, a porcine spinal-cord peptide that can also be regarded as a bombesin-like peptide, exerts stimulating effects on rat uterine smooth muscle and functions as a neuromediator in the neural communication systems of mammals. 

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