Tachykinin peptides

Tachykinins excite neurons, evoke behavioral responses, are potent vasodilators, and contract (directly or indirectly) many smooth muscles. Tachykinins are from ten to twelve residues long.

The two human tachykinin genes are called TAC1 and TAC3 for historical reasons, and are equivalent to Tac1 and Tac2 of the mouse, respectively. TAC1 encodes neurokinin A (formerly known as substance K), neuropeptide K (which has also been called neurokinin K), neuropeptide gamma, and Substance P. Alpha, beta, and gamma splice forms are produced; the alpha form lacks exon 6 and the gamma form lacks exon 4. All three splice forms of TAC1 produce substance P, but only the beta and gamma forms produce the other three peptides. Neuropeptide K and neuropeptide gamma are N-terminally longer versions of neurokinin A that appear to be final peptide products in some tissues.

TAC3 encodes neurokinin B.

The best known tachykinin is Substance P.

Receptors

There are three known mammalian tachykinin receptors termed NK₁, NK₂ and NK₃. All are members of the 7 transmembrane g protein-coupled family of receptors and induce the activation of phospholipase C, producing inositol triphosphate. NK₁, NK₂ and NK₃ selectively bind to substance P, neurokinin A, and neurokinin B, respectively. Whilst the receptors are not specific to any individual tachykinin, they do have differing affinity for the tachykinins:

• NK₁: SP > NKA > NKB
• NK₂: NKA > NKB > SP
• NK₃: NKB > NKA > SP

Antagonists of neurokinin-1 (NK₁) receptors (NK1 receptor antagonists), through which substance P acts, have been proposed to belong to a new class of antidepressants, while NK₂ antagonists have been proposed as anxiolytics and NK₃ antagonists have been proposed as antipsychotics.

Tachykinin peptides are also involved in inflammation, and tachykinin receptor antagonists have been researched for use in treating inflammatory conditions such as asthma and irritable bowel syndrome. The main use for which these antagonist drugs have been applied so far, however, is as antiemetics, in both human and veterinary medicine.

Examples of tachykinin antagonists include:

• Aprepitant
• Casopitant
• Fosaprepitant
• Maropitant
• Nepadutant
• Osanetant
• Saredutant
• Talnetant