Neurokinin A

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). 

Capsaicin, an active ingredient in red pepper, is well known for its ability to release and deplete substance P in sensory C fibers. However, this action is not specific for substance P, as neurokinin A, calcitonin gene-related peptide (CGRP), and somatostatin also are released. 

C-fibre afferents from the aitways contain peptide tachykinin transmitters such as substance P (SP) and neurokinins A and B (NKA and NKB). Stimulation of these nerves can also cause local release of these mediators at their peripheral terminal, allowing them to enhance the activity of the RARs. SP, NKA and NKB act at the tachykinin receptors (NK4-NK3), and so understandably, antagonists for NK2 in particular appear promising in cough. 

The neuropeptides are peptides acting as neurotransmitters. Some form families such as the tachykinin family with substance P, neurokinin A and neurokinin B, which consist of 11 or 12 amino acids and possess the common carboxy-terminal sequence Phe-X-Gly-Leu-Met-CONH2. Substance P is a transmitter of primary afferent nociceptive neurones. The opioid peptide family is characterized by the C-terminal sequence Tyr-Gly-Gly-Phe-X. Its numerous members are transmitters in many brain neurones. Neuropeptide Y (NPY), with 36 amino acids, is a transmitter (with noradrenaline and ATP) of postganglionic sympathetic neurones. 

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

The common C-terminal amino acid sequence required for exerting activity at tachykinin receptors is shown in bold endokinin C and D lack the C-terminal Met and are almost devoid of affinity at these receptors. In red, the sequence of neurokinin A of which neuropeptide-gamma and neuropeptide-kappa are elongated forms and neurokinin A (3-10) is a product of beta or gamma-TAC1 mRNAs or an NKA metabolite active at tachykinin receptors. In blue, the sequence of human HK-1 of which endokinin A and B are elongated forms. 

Some propeptides lead to the production of different, in terms of receptor affinities, peptides (substance P and neurokinin A act on neurokinin 1 and 2 receptors, respectively). 

Different peptides from the same gene product (met and leu enkephalin, substance P and neurokinin A). The former two act on the same receptor, the delta opioid receptor, whereas the latter act on different receptors, the neurokinin 1 and 2 receptors. Despite this, the receptors for the neurokinins produce the same direction of effect, a slow depolarisation, even though their distribution differs. 

These are a family of peptides which include substance P, isolated in 1931 but only sequenced in 1971. This peptide has been extensively studied since it was the first major peptide to be extracted from brain but only now are useful antagonists becoming available. Two closely related peptides were then isolated from mammalian tissues and can be added to a number of other tachykinins, many of which are found in amphibians. The name tachykinins originated from the vasoactive effects of substance P but the nomenclature has been resolved into calling the three major mammalian peptides substance P, neurokinin A (NKA) and neurokinin B (NKB) with the corresponding receptors being numbered 1 to 3. The order of potencies at the three receptors as follows ... 

Shore, S.A. and Drazen, J.M. (1989). Degradative enzymes modulate airway responses to intravenous neurokinins A and B. J. Appl. Physiol. 67, 2504-2511. 

Non-peptidic tachykinine antagonists were converted to photoprobe ligands by Ward. First, a piperidine derivative, CP-99,994 (Glaxo) was appended with a diazirine photophore (6, Fig. 7) to study SP (NK1) receptors [74]. A similar modification on a neurokinin A antagonist, SR 48968 (Sanofi) produced a photoligand (5, Fig. 7) in order to investigate NK2 receptor proteins [75]. 

Substance P, calcitonin-gene-related peptide (CGRP), and neurokinin A have been identified by immunocytochemistry in primary sensory neurones and in cutaneous sensory nerve terminals and these are often in close proximity to mast cells [54, 56], For example, in Lewis rats that were infected with the parasitic larvae of Nippostrongylis brasiliensis in order to induce a proliferation of mucosal mast cells, nearly two-thirds of the lamina propria mast cells were in intimate contact with peptidergic nerves containing SP and CGRP, while an additional 20% of the mast cells were within 2 gm [54], All three peptides are... 

A5 and C primarily project to lamina II and V of the dorsal horn, where they synapse onto local interneurons or directly onto upward-projecting neurons (figure 8.1). These primary afferents release a number of neurotransmitters to relay pain, including glutamate, aspartate, substance P, neurokinin A and B, and calcitonin gene-related peptide (table 8.1). NMDA, non-NMDA and neurokinin receptors are involved in re-... 

Other more recent examples of new receptor subt)rpes include neurokinin, melanocortin and somatostatin receptor subt)q)es. Neurokinins (substance P, neurokinin A and neurokinin B) act at three receptor subtypes NK, NK2 and NK3. Selective ligands are being... 

Substance P (SP) is a member of the family of tachykinin peptides that also includes neurokinin A and B. Their respective receptors are tachykinin NKl, tachykinin NK2 and tachykinin NK3. Substance P is best known as a pain neurotransmitter, but it also controls vomiting. In relation to emesis, its sites of localisation include the area postrema and the nucleus tractus solitarius. 

Other members of this family are neurokinin A and neurokinin B. Substance P is an undecapeptide, while neurokinins A and are decapeptides. 

The actions of substance P and neurokinins A and are mediated by three G protein-coupled tachykinin receptors designated NK i, NK 2, and NK 3. Substance P is the preferred ligand for the NK receptor, the predominant tachykinin receptor in the human brain. However, neurokinins A and also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NKi receptors. All three receptor subtypes are coupled to inositol trisphosphate synthesis and calcium mobilization. 

---