Elsevier

Vascular Pharmacology

Volume 45, Issue 4, October 2006, Pages 200-208
Vascular Pharmacology

Characterization of the gene structures, precursor processing and pharmacology of the endokinin peptides

https://doi.org/10.1016/j.vph.2005.08.028Get rights and content

Abstract

The endokinins represent several species-divergent and peripherally located mammalian tachykinins (hemokinin-1 in mouse and rat, endokinin-1 in rabbit and endokinins A and B in humans) and also the tachykinin gene-related peptides. These peptides are all encoded on the preprotachykinin 4 (TAC4) gene. Their complementary DNA sequences, gene structures and expression profiles have been determined from a number of different mammalian species. They are all flanked by adjacent upstream and downstream dibasic cleavage sites in their respective precursor proteins, except for human EKA/B that instead possesses a N-terminal monobasic cleavage site. Evidence for differential processing in the periphery at the N-terminal cleavage site of the tachykinins could explain why in humans the evolutionary pressure to maintain the N-terminal dibasic cleavage site of EKA/B has been lost. Furthermore, the TAC4 encoded tachykinins all exhibit a remarkable selectivity and potency for the highly species conserved tachykinin NK1 receptor, similar to that of substance P. Particular consideration is also given to the potential interactions of the endokinins with the short NK1 receptor isoform and to speculation of whether there could be an “endokinin-sensitive” NK1 binding site.

Introduction

The mammalian tachykinins have included, until recently, only the three members substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) (Severini et al., 2002, Page, 2004). By definition these short peptides (10–11 amino acid residues in length) all share the same conserved hydrophobic C-terminal region, FXGLM-NH2, where X is either an aromatic or a β-branched aliphatic amino acid residue. Their N-terminals are significantly divergent and hydrophilic, however, it is of particular note that each of these tachykinins are identical across the mammalian species (Page et al., 2003). Traditionally, the tachykinins have been classified as neurotransmitters and in the periphery SP and NKA have been found in discrete neurons innervating smooth muscle beds and in immune cells (reviewed by Page, 2004, Page, 2005), while NKB had only been found in the central nervous system (Moussaoui et al., 1992, Patacchini et al., 2000). Recently, this conceived dogma for NKB was challenged when the placenta, a tissue devoid of nerves, was found to be the major source of NKB gene expression (Page et al., 2000, Page et al., 2001). Moreover, since the discovery of a third preprotachykinin gene (TAC4), the number of tachykinins has more than doubled to reveal several species-divergent and peripherally expressed peptides. This group includes hemokinin-1 (HK-1) in mouse and rat (Zhang et al., 2000, Kurtz et al., 2002, Page et al., 2003), endokinin-1 (EK-1) in rabbit (Page, 2004), and endokinin A (EKA), EKB (Page et al., 2003), human HK-1 (hHK-1) and hHK4–11 (Kurtz et al., 2002) in humans. Additionally, three orphan tachykinin gene-related peptides are identified on TAC4, in rabbit, EK-2 (Page, 2004) and in humans, EKC and EKD (Page et al., 2003).

Section snippets

Endokinin genes and their peptides

Two tachykinin precursor genes were originally identified encoding the mammalian tachykinins, preprotachykinin 1 (TAC1) and 3 (TAC3) (Nawa et al., 1983, Kotani et al., 1986). TAC1 encodes both SP (RPKPQQFFGLM-NH2) and NKA (HKTDSFVGLM-NH2) (Nawa et al., 1983, Nawa et al., 1985), of which four alternatively spliced mRNA transcripts (α, β, γ and δTAC1) are produced by the alternative splicing of exons 4 and 6 (Nawa et al., 1983, Nawa et al., 1985, Kawaguchi et al., 1986, Harmar et al., 1990). All

TAC4 precursor processing

The expression pattern for the mRNA of the mouse, rat and human TAC4 precursors clearly shows the potential for synthesis and action of the hemokinin and endokinin peptides in a wide variety of cells and tissues. Nevertheless, even though mRNA levels are generally a good reflection of translated protein, they may not always be a good measure of the precise amounts of active peptide, because these will be determined by a number of key factors including the manner of processing, turnover, storage

Pharmacology of the endokinins

In humans, the loss of the N-terminal dibasic cleavage site remains a baffling phenomenon, although it does appear to have some biological function. In this regard, of particular significance is the testing of an extended form of the C-terminal decapeptide sequence of EKA/B, TEAETWEGAGPSIQLQLQEVKTGKASQFFGLM-NH2 that showed a greater affinity for the NK1 receptor than just the C-terminal decapeptide of EKB (Page et al., 2003). Therefore, differential processing of EKA/B in a range of different

Conclusion

There is an expanding repertoire of mammalian tachykinins, which through a variety of TAC genes, gene splicing events, and subsequent peptide processing allows many different configurations of the parent precursor and parent peptide to be produced. Even though only three tachykinin receptors have been identified with certainty, it is possible that these can be modified not only by gene splicing events, but be present in different conformations. Many of these processes appear to be

Acknowledgements

The Medical Research Council (UK) supported this work.

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