Neurokinins

Definition
The neurokinins are a family of neuropeptides which includes substance P (SP) and the two structurally related peptides, neurokinin A (NKA) and neurokinin B (NKB). These neurotransmitters appear to play a key role in the regulation of emotions, and antagonists of their receptors may be novel psychotropic drugs of the future1.

Related peptides
These carboxyl terminal-amidated peptides are derived from two preprotachykinin genes - the PPT-A gene encodes the sequences of Substance P, Neurokinin A, and neuropeptide K and the PPT-B gene encodes the sequence of Neurokinin B1.

Discovery
In 1931 von Euler and Gaddum suggested the existence of SP in the extract of mammalian guts. The structure was finally confirmed and sequenced by Chang et al. in 1971. Subsequently NKA and NKB were both isolated from porcine spinal cord in 1983. The structures were elucidated by the independent contributions of Kimura et al. and Kangawa et al1.

Structural Characteristics
Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.
NKA:His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2,
NKB:Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH2.
The neurokinins are characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is a phenylalanine or a valine1.

Mode of Action
Glutamate, through activation of post-synaptic N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, contributes to neurokinin signaling in the nucleus of the solitary tract (NST) 2. .Once released, SP and NKA exert their biological effects on target cells by interacting with specific receptors, which have been cloned, characterized, and found to have seven transmembrane spanning sequences and to be coupled to G-proteins and the phosphoinositide-signaling pathway. To date, three distinct receptors have been identified, termed neurokinin-1 receptor (NK-1R), neurokinin-2 receptor (NK-2R), and neurokinin-3 receptor (NK-3R). SP preferentially activates the NK-1R, NKA the NK-2R, and neurokinin B the NK-3R; however, at high ligand concentrations each tachykinin can activate each of the tachykinin receptors3.

Functions
Neurokinins exert quite diverse functions in the whole body. For instance, SP acts in the CNS as a pain transmitter and also as a regulator of dopaminergic and adrenergic neurons. In the peripheral system, SP and/or NKA are involved in activation of the immune system, vasodilation, smooth muscle contraction, bronchoconstriction, stimulation of salivary secretion, neurogenic inflammation, and so on1. Neurokinin B may play an important role in the olfactory, gustatory, visceral, and neuroendocrine processing information. Neurokinin B is potent bronchioconstrictor and has neuromodulatory roles in various brain functions. Neurokinin B stimulate the production of immunoglobulins in peripheral B lymphocytes, This conditional response to Neurokinin B is likely due NK-3 receptors present only following co-culture and activation3.

References
1.Takaya. T (1996). Discovery of neurokinin antagonists. Pure & Appl. Chem., 68(4):875-880.
2.Colin I, Blondeau C, Baude A.(2002). Neurokinin release in the rat nucleus of the solitary tract via NMDA and AMPA receptors. Neuroscience., 115(4)1023-1033
3.Renzi D, Pellegrini B, Tonelli F, Surrenti C, Calabrò A (2000). Substance P (Neurokinin-1) and Neurokinin A (Neurokinin-2) Receptor Gene and Protein Expression in the Healthy and Inflamed Human Intestine. Am J Pathol., 157(5):1511-1522