Tachykinins

In this chapter, we will review our current understanding of the pulmonary effects of a specific class of prophlogistic neurotransmitters known as the tachykinins and of two homeostatic neurotransmitters, vasoactive intestinal peptide (VIP) and nitric oxide (NO ). We will pay special attention to the roles of these transmitters in inflammatory obstructive airway disorders. Each class of neurotransmitter will be considered separately. 

We will first consider the synthesis, release and localization of tachykinins in the airways. Next we will examine the impact of tachykinin degradation and tachykinin receptor expression on the physiological actions of these neurotransmitters in the airways. Finally, we will review the evidence for modulation of the effects of tachykinins in the inflammatory microenvironment (e.g. in asthma) and we will describe the interactions of tachykinins with mast cells and lymphocytes. 

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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). 

Tachykinins and Substance P. The tachykinins (82) include the undecapeptide, substance P,... 

H-Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2. Physalaemin, eledoisin, kassinin, SCYl, and SCYll are nonmammalian tachykinins. Two larger peptides have been identified, neuropeptide K (328) and neuropeptide y (329), both of which interact with tachykinin receptors (Table 19). The NKA sequence is contained within the carboxy-terrninal sequences of both neuropeptide K and neuropeptide y. Like other neuroactive peptides, tachykinin peptide precursors are synthesized ribosomaHy and transported to nerve terminals where further processing occurs. 

Three tachykinin GPCRs, NK, NK, and NK, have been identified and cloned. AH are coupled to phosphatidjhnositol hydrolysis. The NK receptor is selective for substance P (SP) and is relatively abundant in the brain, spinal cord, and peripheral tissues. The NK receptor is selective for NKA and is present in the gastrointestinal tract, urinary bladder, and adrenal gland but is low or absent in the CNS. The NIC receptor is selective for NKB and is present in low amounts in the gastrointestinal tract and urinary bladder, but is abundant in some areas of the CNS, ie, the spinal dorsal bom, soUtary nucleus, and laminae IV and V of the cortex with moderate amounts in the interpeduncular nucleus. Mismatches in the distribution of the tachykinins and tachykinin receptors suggest the possibility of additional tachykinin receptor subtypes. 

A two-site immunometric assay of undecapeptide substance P (SP) has been developed. This assay is based on the use of two different antibodies specifically directed against the N- and C-terminal parts of the peptide (95). Affinity-purified polyclonal antibodies raised against the six amino-terminal residues of the molecule were used as capture antibodies. A monoclonal antibody directed against the carboxy terminal part of substance P (SP), covalently coupled to the enzyme acetylcholinesterase, was used as the tracer antibody. The assay is very sensitive, having a detection limit close to 3 pg/mL. The assay is fiiUy specific for SP because cross-reactivity coefficients between 0.01% were observed with other tachykinins, SP derivatives, and SP fragments. The assay can be used to measure the SP content of rat brain extracts. 

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. 

Nociceptin and orphanin are synonyms for the peptide that acts at an opioid-like receptor. Nociceptin may act by inhibiting tachykinin release from sensory C-fibres, and a clinical trial has started to test its effects on cough. 

Synaptic Transmission Purtnergic System Tachykinins and their Receptors... 

Edg receptors are a group of recently discovered G-protein coupled receptors, which mediate the action of lysophospholipids (sphingosine-1 -phosphate, lysophosphatidic acid). Tachykinins and their Receptors... 

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. 

Substance P is a member of a group of polypeptides known as neurokinins or tachykinins. It is thought to be the primary neurotransmitter for the transfer of sensory information from the periphery to the spinal cord and brain. Substance P as well as neurokinin NKX receptors has been detected in vagal afferent neurons in the area postrema, nucleus tractus solitarius and dorsal motor nucleus of the vagus. Substance P has been shown to increase the firing rate of neurons in the area postrema and nucleus tractus solitarius and to produce retching when applied directly to these areas in animal studies. 

Except substance P (SP), the first mammalian tachykinin (TK) peptide to be sequenced (by Chang and Leeman in 1970), other peptides belonging to TK family have synonyms. This is due to historical reasons,... 

Tachykinins and their Receptors. Table 1 Abbreviations and synonyms of tachykinin peptides, genes, and receptors... 

Tachykinin NH receptor TK N r Neurokinin-1 receptor, substance P receptor... 

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... 

Tachykinin 1 gene TAC1. PPT-A. PPT-i Preprotachykinin A gene, Preprotachykinin I gene... 

Tachykinin 3 gene TAC3. PPT-B. PPT-ii Preprotachykinin B gene, Preprotachykinin II gene... 

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