Characterization of the gene structures, precursor processing and pharmacology of the endokinin peptides
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.
References (58)
- et al.
Cloning of a C-terminally truncated NK-1 receptor from guinea-pig nervous system
Brain Res. Mol. Brain Res.
(2003) - et al.
Preprotachykinin gene expression in the human basal ganglia: characterization of mRNAs and pre-mRNAs produced by alternate RNA splicing
Brain Res. Mol. Brain Res.
(1992) - et al.
A 25 year adventure in the field of tachykinins
Peptides
(2004) - et al.
Pharmacological evaluation of alpha and beta human tachykinin NK(2) receptor splice variants expressed in CHO cells
Eur. J. Pharmacol.
(2004) - et al.
Identification of potential tyrosine-containing endocytic motifs in the carboxyl-tail and seventh transmembrane domain of the neurokinin 1 receptor
J. Biol. Chem.
(1997) - et al.
Pharmacological profile of hemokinin 1: a novel member of the tachykinin family
Life Sci.
(2002) - et al.
Centrally administered hemokinin-1 (HK-1), a neurokinin NK1 receptor agonist, produces substance P-like behavioral effects in mice and gerbils
Neuropharmacology
(2003) - et al.
Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins
J. Mol. Biol.
(1978) The ʽseptide-sensitive' tachykinin receptor: still an enigma
Trends Pharmacol. Sci.
(1995)- et al.
Tachykinins regulate the function of platelets
Blood
(2004)
Identification and cDNA sequence of delta-preprotachykinin, a fourth splicing variant of the rat substance P precursor
FEBS Lett.
Negative feedback on the effects of stem cell factor on hematopoiesis is partly mediated through neutral endopeptidase activity on substance P: a combined functional and proteomic study
Blood
Sequence analysis of cloned cDNA for rat substance P precursor: existence of a third substance P precursor
Biochem. Biophys. Res. Commun.
Identification, localization and receptor characterization of novel mammalian substance P-like peptides
Gene
Neurokinin B causes concentration-dependent relaxation of isolated human placental resistance vessels
Regul. Pept.
Multiple tachykinins are produced and secreted upon post-translational processing of the three substance P precursor proteins, alpha-, beta-, and gamma-preprotachykinin. Expression of the preprotachykinins in AtT-20 cells infected with vaccinia virus recombinants
J. Biol. Chem.
Differential expression of two isoforms of the neurokinin-1 (substance P) receptor in vivo
Brain Res.
Distribution of neurokinin B in rat spinal cord and peripheral tissues: comparison with neurokinin A and substance P and effects of neonatal capsaicin treatment
Neuroscience
Expression of hemokinin 1 mRNA by murine dendritic cells
J. Neuroimmunol.
New challenges in the study of the mammalian tachykinins
Peptides
A regulatory role for neurokinin B in placental physiology and pre-eclampsia
Regul. Pept.
Precursors for peptide hormones share common secondary structures forming features at the proteolytic processing sites
FEBS Lett.
Major metabolites of substance P degraded by spinal synaptic membranes antagonize the behavioral response to substance P in rats
J. Pharm. Sci.
Neuropeptide K: isolation, structure and biological activities of a novel brain tachykinin
Biochem. Biophys. Res. Commun.
The N-terminal domain of substance P is required for complete homologous desensitization but not phosphorylation of the rat neurokinin-1 receptor
Neuropeptides
T-cell developmental blockage by tachykinin antagonists and the role of hemokinin 1 in T lymphopoiesis
Blood
Injection of substance P (SP) N-terminal fragment SP(1–7) into the ventral tegmental area modulates the levels of nucleus accumbens dopamine and dihydroxyphenylacetic acid in male rats during morphine withdrawal
Neurosci. Lett.
Processing of procorticotropin-releasing hormone (pro-CRH): molecular forms of CRH in normal and preeclamptic pregnancy
J. Clin. Endocrinol. Metab.
Pharmacological profile of the novel mammalian tachykinin, hemokinin 1
Br. J. Pharmacol.
Cited by (43)
Role of hemokinin-1 in health and disease
2017, NeuropeptidesDistribution of hemokinin-1 in the rat trigeminal ganglion and trigeminal sensory nuclear complex
2017, Archives of Oral BiologyCitation Excerpt :A new mammalian tachykinin peptide encoded in a preprotachykinin gene, TAC4, was identified in mouse bone marrow cells and designated as hemokinin-1 (HK-1) (Zhang, Lu, Furlonger, Wu, & Paige, 2000). HK-1 exhibits structural homology with known members of the tachykinin family, of which peptides share a carboxyl-terminal F-X-G-L-M-amide motif and more varied amino-terminals (Page, 2004; Page, 2005; Page, 2006). A representative of the tachykinin peptide family is substance P (SP), and its function has been well characterized.
Role of substance P in the cardiovascular system
2016, NeuropeptidesCitation Excerpt :Since the discovery of a new preprotachykinin gene in year 2000, the number of known tachykinins rapidly increased. These newly described peptides are called endokinins and include hemokinin-1 in mouse, rat and human, endokinin-1 in rabbit, and endokinin A and B in humans (Page, 2006). SP was one of the most extensively studied active substance during the half-century since its discovery, and for many years, it was believed to be the only mammalian tachykinin considered as a neuropeptide.
Hemokinin-1 is an important mediator of endotoxin-induced acute airway inflammation in the mouse
2015, PeptidesCitation Excerpt :The preprotachykinin C (Tac4) gene was discovered in 2000 providing the newest member of the tachykinin family [43]. The Tac4 gene encodes several related peptides in different species, such as hemokinin-1 (HK-1) in mice, endokinin-1 and -2 (EK-1, EK-2) in rabbits, as well as endokinins A-D (EKA, EKB, EKC, EKD) in humans [31]. The 11-amino-acid-long HK-1 shows structural similarities to substance P (SP) resulting in strong immunological crossreactivity with anti-SP antibodies [31] that might have led to several inadequate conclusions in the literature.
Hemokinin-1 mediates pruriceptive processing in the rat spinal cord
2014, Neuroscience