MinireviewTachykinins and tachykinin receptors: a growing family
Introduction
Tachykinins (TKs) are a family of closely related peptides whose best known members are substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). For many years, the tachykinins were considered almost exclusively as peptides of neuronal origin. NKB is present in the central nervous system and the spinal cord Kangawa et al., 1983, Moussaoui et al., 1992, Goubillon et al., 2000, Patacchini et al., 2000 while SP and NKA are found in the central nervous system and also in primary afferent sensory neurons supplying a number of peripheral tissues Holzer, 1988, Maggi and Meli, 1988, Lundberg, 1996, Patak et al., 2000a. SP and NKA are released from nerve endings at both the spinal cord and the peripheral level and play a role as excitatory neurotransmitters Lembeck and Holzer, 1979, Maggi, 1991, Otsuka and Yoshioka, 1993, Meini and Maggi, 1994, Patacchini et al., 1998, Patak et al., 2000a.
Capsaicin-sensitive sensory nerves have been considered as the principal source of TKs at the peripheral level Jancso et al., 1977, Maggi and Meli, 1988, Lundberg, 1996, Patacchini et al., 1998. However, recent evidence shows that other neuronal and non-neuronal sources of TKs exist in the periphery. Thus, it has been found that tachykinin expression can occur in capsaicin-resistant large neurons bearing Aβ-fibers following neuronal plasticity induced by inflammation of somatic areas (Neumann et al., 1996) and in other kinds of capsaicin-resistant neurons in the airways Hunter et al., 2000, Myers et al., 2002, Carr et al., 2002 and the enteric nervous system Holzer and Holzer-Petsche, 1997, Lomax and Furness, 2000. SP appears to be present in human endothelial cells (Linnik and Moskowitz, 1989; see Maggi, 1997, for a review), human and mouse Leydig cells (Chiwakata et al., 1991) and different types of inflammatory and immune cells from human, rat and mouse Aliakbari et al., 1987, Pascual and Bost, 1990, Ho et al., 1997, Lai et al., 1998. SP and/or NKA are also expressed in enterochromaffin cells (Simon et al., 1992), epithelial cells (Chu et al., 2000), fibroblasts (Bae et al., 2002), intestinal and airway smooth muscle cells Khan and Collins, 1994, Maghni et al., 2003, and in various types of female reproductive organs Patak et al., 2003, Pintado et al., 2003. Recent reports have also indicated the presence of NKB mRNA in the human and rat placenta (Page et al., 2000) and uterus Pinto et al., 2001, Patak et al., 2003 as well as in other types of non-neuronal reproductive cells from mice (Pintado et al., 2003). Moreover, the new members of the family hemokinin-1 (HK-1) and its human orthologs HK-1 and the endokinins (EKs) A, B, C and D are primarily expressed in non-neuronal cells Zhang et al., 2000, Kurtz et al., 2002, Page et al., 2003.
Recent advances in the field of tachykinins have considerably increased interest in this peptide family. A pathophysiological role of NKB has been largely questioned, but a recent report has established a correlation between excessive placental secretion of NKB and pre-eclampsia (Page et al., 2000). Other reports suggest that tachykinins may facilitate cancer cell growth Singh et al., 2000, Friess et al., 2003. Studies in SP/NKA knockout mice or mice in which the tachykinin NK1 receptor has been deleted have confirmed the important role of these neuropeptides as mediators of neurogenic inflammation Cao et al., 1998, De Felipe et al., 1998. In addition, the availability of the SP/NKA knockout model has permitted the observation that tachykinin expression in both sensory neurons and hematopoietic cells is needed for the development of inflammation following antigen-antibody complex formation, at least in the airways (Chavolla-Calderon et al., 2003). Tachykinins appear to be involved in the regulation of hematopoiesis Rameshwar et al., 1993, Rameshwar, 1997, Zhang et al., 2000, Bandari et al., 2003a, Bandari et al., 2003b and TK levels are augmented in macrophages and lymphocytes from HIV patients (Ho et al., 2002). These data, and the observation that tachykinin expression is increased or induced in different inflammatory and infectious diseases (Kennedy et al., 2003; see Lecci and Maggi, 2003 for review), suggest that these molecules may act as paracrine or endocrine factors and play a role in neuroimmunomodulation.
The three types of tachykinin receptors, denoted NK1, NK2 and NK3 receptors, are heterogeneously distributed within each species. The NK1 receptor is widely expressed at both the central and the peripheral level and is present in neurons, vascular endothelial cells, muscle and different types of immune cells, among others Stewart-Lee and Burnstock, 1989, Tsuchida et al., 1990, Ho et al., 1997, Lai et al., 1998, Patacchini and Maggi, 2001. The NK1 receptor is constitutively expressed in most of these cells, while an inducible receptor exists in bone marrow cells (Bandari et al., 2002). The tachykinin NK2 receptor is primarily detected in the periphery and its expression in the CNS appears to be restricted to specific brain nuclei Naline et al., 1989, Tsuchida et al., 1990, Pennefather et al., 1993, Croci et al., 1998, Saffroy et al., 2001, Saffroy et al., 2003. In contrast, the tachykinin NK3 receptor is mainly expressed in the CNS and has only been detected in certain peripheral tissues, such as the human and rat uterus, the human skeletal muscle, lung and liver, the rat portal and mesenteric vein, and certain enteric neurons from the gut of different species Tsuchida et al., 1990, Massi et al., 2000, Page and Bell, 2002, Patak et al., 2003, Fioramonti et al., 2003, Lecci and Maggi, 2003. The discovery of new tachykinins has led to the suggestion that more, still unidentified tachykinin receptors may exist Zhang et al., 2000, Page et al., 2003. The major aim of the present review is to provide an overview of the current knowledge on tachykinins and their receptors.
Section snippets
Tachykinin genes
The three classical members of the mammalian tachykinin family are SP, NKA and NKB Chang et al., 1971, Kangawa et al., 1983, Nawa et al., 1984, Tatemoto et al., 1985. In addition, recent evidence suggests that the N-terminally extended forms of NKA, named neuropeptide K (NPK) and neuropeptide γ (NPγ), are also biologically active peptides Kage et al., 1988, Carter and Krause, 1990, Burcher et al., 1991, Saffroy et al., 2003. Four of these peptides, SP, NKA, NPK and NPγ, are encoded by the
Are there more tachykinins?
The family of tachykinins and related peptides is one of the more extended protein families in Metazoa (Severini et al., 2002). Tachykinins have been found in many different species across of Bilateria, from invertebrates to mammals Erspamer and Anastasi, 1962, Nassel, 1999, Liu et al., 2000, Holmgren and Jensen, 2001, Severini et al., 2002, suggesting that the tachykinin motif has been widely exploited throughout evolution. The recent availability of whole genomes from different organisms
Tachykinin receptor genes
Tachykinins interact with specific membrane receptors belonging to the family of G protein-coupled receptors (GPCRs) Nakanishi, 1991, Gerard et al., 1993, Krause et al., 1994, Maggi, 1995. Currently, three distinct tachykinin receptors, NK1, NK2 and NK3, have been cloned in different species including human (Table 3) Gerard et al., 1991, Takeda et al., 1991, Takahashi et al., 1992, Gerard et al., 1990, Buell et al., 1992.
The genes encoding the three mammalian tachykinin receptors have a similar
Are there more tachykinin receptors?
The existence of additional tachykinin receptors has been largely questioned but all attempts to find a fourth TK receptor have been unsuccessful. However, the recent identification of new mammalian tachykinins has reopened the debate Zhang et al., 2000, Page et al., 2003. In fact, several experimental data are difficult to explain by considering the three known tachykinin receptors. For example EKC and EKD have a very weak activity at the NK1, NK2 and NK3 receptors. NKB shows different
Conclusions
The tachykinins constitutes one of the largest peptide families in Metazoa. Tachykinin and tachykinin receptors have been highly conserved throughout evolution and are present in most species along Bilateria. The high level of conservation during millions of years argues for an important biological function that is perhaps, still only partially understood. In this context, recent exciting findings in the field of tachykinins have considerably increased the interest and the scope of these
References (135)
- et al.
Selective localization of vasoactive intestinal peptide and substance P in human eosinophils
Biochemical and Biophysical Research Communications
(1987) - et al.
Crosstalk between neurokinin receptors is relevant to hematopoietic regulation: cloning and characterization of neurokinin-2 promoter
Journal of Neuroimmunology
(2003) - et al.
Hematopoietic growth factor inducible neurokinin-1 type: a transmembrane protein that is similar to neurokinin 1 interacts with substance P
Regulatory Peptides
(2003) - et al.
Differences in the expression of neurokinin receptor in neural and bone marrow mesenchymal cells: implications for neuronal expansion from bone marrow cells
Neuropeptides
(2002) - et al.
Cloning of a C-terminally truncated NK-1 receptor from guinea-pig nervous system
Brain Research and Molecular Brain Research
(2003) - et al.
Molecular characterisation, expression and localisation of human neurokinin-3 receptor
FEBS Letters
(1992) - et al.
Neuropeptide gamma, the most potent contractile tachykinin in human isolated bronchus, acts via a ‘non-classical’ NK2 receptor
Neuropeptides
(1991) - et al.
Pharmacological profile of hemokinin 1: a novel member of the tachykinin family
Life Sciences
(2002) - et al.
Identification of a tachykinin NK (2) receptor splice variant and its expression in human and rat tissues
Life Sciences
(2002) - et al.
Substance P and its receptor neurokinin 1 expression in asthmatic airways
Journal of Allergy and Clinical Immunology
(2000)