The Mammalian Tachykinins and Their Receptors: Structure-Activity Relationship of the Mammalian Tachykinins

Abstract

The tachykinins are a family of naturally occuring bioactive peptides, which share the common C-terminal amino acid sequence, Phe-X-Gly-Leu-Met-NH₂ (Fig.1) and exhibit a wide spectrum of biological actions such as smooth muscle contraction, sialogogic action and hypotension (Ersparmer, 1981). Until recently, substance P (SP)(X=Phe) has been the only known tachykinin shown to be present in the mammalian tissues. The accumulating evidence suggest that SP is a neurotransmitter or neuromodulator in the central and peripheral nervous systems (Otsuka and Konishi, 1975; Pernow, 1983). We have recently determined the amino acid sequences of two additional and novel tachykinins (X=Va1), neurokinin A (NKA) and neurokinin B (NKB), which are remarkably similar to kassinin (Kimura et al., 1983). The identical peptides were independently reported and named differently; NKA as neuromedin L or substance K (Maggio et al., 1983; Minamino et al., 1984; Nawa et al., 1983) and NKB as neuromedin K (Kangawa et al., 1983). Pharmacologically, it was revealed that both neurokinins (NKs) possess the typical tachykinin activities and SP-E type ligand characteristics using peripheral tissues (Hunter and Maggio, 1984; Kimura et al., 1984; Nawa et al., 1984) and central nervous tissues (Buch et al., 1984; Mantyh et al., 1984; Quirion and Pilapil, 1984; Torrens et al., 1984). Electrophysiologically, it was found that both NKA and NKB have potent excitatory actions on neurons in the isolated spinal cord of neuborn rat (Matsuto et al., 1984). Moreover, we and others have shown using radioimmunoassay system that NKA and NKB are distributed unevenly in rat central nervous system (Kanazawa et al., 1984; Minamino et al., 1984). Especially, considerable amounts of NKs were found in the spinal cord and localized predominantly in the dorsal horn (Ogawa et al., 1985). Furthermore, the nucleotide sequences of two different SP precursors isolated from bovine striatum have been reported; one contains each copy of SP and NKA (substance K) while the other contains only substance P (Nawa et al., 1983). It was suggested that NKA (SK) may be coreleased with SP from the common precursor and serves as a second type of the endogenous tachykinin in mammalian tissue. These lines of evidence strongly suggested that NKs may act as neurotransmitters or neuromodulators like SP in mammalian central nervous system, especially, in the spinal cord.