Elsevier

Life Sciences

Volume 74, Issue 12, 6 February 2004, Pages 1445-1463
Life Sciences

Minireview
Tachykinins and tachykinin receptors: a growing family

https://doi.org/10.1016/j.lfs.2003.09.039Get rights and content

Abstract

The peptides of the tachykinin family are widely distributed within the mammalian peripheral and central nervous systems and play a well-recognized role as excitatory neurotransmitters. Currently, the concept that tachykinins act exclusively as neuropeptides is being challenged, since the best known members of the family, substance P, neurokinin A and neurokinin B, are also present in non-neuronal cells and in non-innervated tissues. Moreover, the recently cloned mammalian tachykinins hemokinin-1 and endokinins are primarily expressed in non-neuronal cells, suggesting a widespread distribution and important role for these peptides as intercellular signaling molecules. The biological actions of tachykinins are mediated through three types of receptors denoted NK1, NK2 and NK3 that belong to the family of G protein-coupled receptors. The identification of additional tachykinins has reopened the debate of whether more tachykinin receptors exist. In this review, we summarize the current knowledge of tachykinins and their receptors.

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)

  • H. Friess et al.

    Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer

    Laboratory Investigations

    (2003)
  • N.P. Gerard et al.

    Molecular aspects of the tachykinin receptors

    Regulatory Peptides

    (1993)
  • N.P. Gerard et al.

    The human neurokinin A (substance K) receptor. Molecular cloning of the gene, chromosome localization, and isolation of cDNA from tracheal and gastric tissues

    Journal of Biological Chemistry

    (1990)
  • A.J. Harmar et al.

    cDNA sequence of human beta-preprotachykinin, the common precursor to substance P and neurokinin A

    FEBS Letters

    (1986)
  • A.J. Harmar et al.

    Identification and cDNA sequence of delta-preprotachykinin, a fourth splicing variant of the rat substance P precursor

    FEBS Letters

    (1990)
  • H. Hastrup et al.

    Septide and neurokinin A are high affinity ligands on the NK-1 receptor: evidence from homologous versus heterologous binding analysis

    FEBS Letters

    (1996)
  • A.D. Hershey et al.

    Organization, structure, and expression of the gene encoding the rat substance P receptor

    Journal of Biological Chemistry

    (1991)
  • S. Holmgren et al.

    Evolution of vertebrate neuropeptides

    Brain Research Bulletin

    (2001)
  • P. Holzer

    Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

    Neuroscience

    (1988)
  • P. Holzer et al.

    Tachykinins in the gut. Part I. Expression, release and motor function

    Pharmacology and Therapeutics

    (1997)
  • K. Kangawa et al.

    Neuromedin K: a novel mammalian tachykinin identified in porcine spinal cord

    Biochemical and Biophysical Research Communications

    (1983)
  • I. Khan et al.

    Fourth isoform of preprotachykinin messenger RNA encoding for substance P in the rat intestine

    Biochemical and Biophysical Research Communications

    (1994)
  • Y. Kawaguchi et al.

    Sequence analysis of cloned cDNA for rat substance P precursor: existence of a third substance P precursor

    Biochemical and Biophysical Research Communications

    (1986)
  • M.M. Kurtz et al.

    Identification, localization and receptor characterization of novel mammalian substance P-like peptides

    Gene

    (2002)
  • J.P. Lai et al.

    Human lymphocytes express substance P and its receptor

    Journal of Neuroimmunology

    (1998)
  • S. Lecat et al.

    Mutations in the extracellular amino-terminal domain of the NK2 neurokinin receptor abolish cAMP signaling but preserve intracellular calcium responses

    Journal of Biological Chemistry

    (2002)
  • A. Lecci et al.

    Tachykinins as modulators of the micturition reflex in the central and peripheral nervous system

    Regulatory Peptides

    (2001)
  • M.D. Linnik et al.

    Identification of immunoreactive substance P in human and other mammalian endothelial cells

    Peptides

    (1989)
  • L. Liu et al.

    Bufokinin: immunoreactivity, receptor localization and actions in toad intestine and mesenteric circulation

    Peptides

    (2000)
  • M.R. MacDonald et al.

    Posttranslational processing of alpha-, beta-, and gamma-preprotachykinins. Cell-free translation and early posttranslational processing events

    Journal of Biological Chemistry

    (1988)
  • C.A. Maggi

    The mammalian tachykinin receptors

    General Pharmacology

    (1995)
  • C.A. Maggi

    The effects of tachykinins on inflammatory and immune cells

    Regulatory Peptides

    (1997)
  • C.A. Maggi

    Principles of tachykininergic co-transmission in the peripheral and enteric nervous system

    Regulatory Peptides

    (2000)
  • C.A. Maggi et al.

    The sensory-efferent function of capsaicin-sensitive sensory neurons

    General Pharmacology

    (1988)
  • C.A. Maggi et al.

    The dual nature of the tachykinin NK1 receptor

    Trends in Pharmacological Sciences

    (1997)
  • M. Massi et al.

    The psychopharmacology of tachykinin NK-3 receptors in laboratory animals

    Peptides

    (2000)
  • S.M. Moussaoui et al.

    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

    (1992)
  • D.R. Nassel

    Tachykinin-related peptides from invertebrates: a review

    Peptides

    (1999)
  • N.M. Page et al.

    The human tachykinin NK1 (short form) and tachykinin NK4 receptor: a reappraisal

    European Journal of Pharmacology

    (2002)
  • T. Palanche et al.

    The neurokinin A receptor activates calcium and cAMP responses through distinct conformational states

    Journal of Biological Chemistry

    (2001)
  • R. Patacchini et al.

    Tachykinin NK(2) receptor mediates contraction and ion transport in rat colon by different mechanisms

    European Journal of Pharmacology

    (2001)
  • S.F. Altschul et al.

    Gapped BLAST and PSI-BLAST: a new generation of protein database search programs

    Nucleic Acids Research

    (1997)
  • S.J. Bae et al.

    Substance P induced preprotachykinin-a mRNA, neutral endopeptidase mRNA and substance P in cultured normal fibroblast

    International Archives of Allergy and Immunology

    (2002)
  • F. Bellucci et al.

    Pharmacological profile of the novel mammalian tachykinin, hemokinin 1

    British Journal of Pharmacology

    (2002)
  • L. Caberlotto et al.

    Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain

    European Journal of Neurosciences

    (2003)
  • M.L. Candenas et al.

    Changes in the expression of tachykinin receptors in the rat uterus during the course of pregnancy

    Biology of Reproduction

    (2001)
  • Y.Q. Cao et al.

    Primary afferent tachykinins are required to experience moderate to intense pain

    Nature

    (1998)
  • M.J. Carr et al.

    Expression of tachykinins in nonnociceptive vagal afferent neurons during respiratory viral infection in guinea-pigs

    American Journal of Respiratory and Critical Care Medicine

    (2002)
  • M.S. Carter et al.

    Structure, expression, and some regulatory mechanisms of the rat preprotachykinin gene encoding substance P, neurokinin A, neuropeptide K, and neuropeptide gamma

    Journal of Neuroscience

    (1990)
  • M.M. Chang et al.

    Aminoacid sequence of substance P

    Nature

    (1971)
  • Cited by (0)

    View full text