Minireview
Tachykinins and tachykinin receptors:a growing family
Jocelyn N.Pennefather a ,Alessandro Lecci b ,M.Luz Candenas c ,Eva Patak d ,
Francisco M.Pinto c,*,Carlo Alberto Maggi b
a
Department of Pharmaceutical Biology and Pharmacology,Victorian College of Pharmacy,Monash University,
Parkville,Victoria 3052,Australia b Pharmacology Department,Menarini Ricerche SpA Research Laboratories,Via Rismondo 12/A,50131Florence,Italy c Instituto de Investigaciones Qu?
′micas,Centro de Investigaciones Cient?′ficas Isla de La Cartuja,Avda.Americo Vespucio s/n,41092Sevilla,Spain d Department of Anaesthetics,Royal Women’s Hospital,Carlton,Victoria 3053,Australia
Received 29July 2003;accepted 5September 2003Abstract
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-1and 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 NK 1,NK 2and NK 3that 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.
D 2003Elsevier Inc.All rights reserved.
Keywords:Tachykinins;Tachykinin receptors;Substance P;Neurokinin A;Neurokinin B;Endokinins A,B,C,D 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 0024-3205/$-see front matter D 2003Elsevier Inc.All rights reserved.doi:10.1016/j.lfs.2003.09.039
*Corresponding author.Tel.:+34-95-4480565;fax:+34-95-4460565.
E-mail address:francisco.pinto@iiq.cartuja.csic.es (F.M.Pinto).
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Life Sciences 74(2004)
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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)
SP and NKA are found in the central nervous system and also in primary afferent sensory neurons
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 A h-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-1and 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 NK1receptor 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,b)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,2003for 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,NK2and NK3receptors,are heterogeneously distributed within each species.The NK1receptor is widely expressed at both the central and the
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J.N.Pennefather et al./Life Sciences74(2004)1445–14631447 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 NK1receptor is constitutively expressed in most of these cells,while an inducible receptor exists in bone marrow cells(Bandari et al.,2002).The tachykinin NK2receptor 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.,2001,2003).In contrast,the tachykinin NK3receptor 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.
Human tachykinins
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 g(NP g),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 NP g,are encoded by the preprotachykinin-A(PPT-A)gene(Table1)(Nawa et al.,1984;Carter and Krause,1990).The human gene consists of seven exons and the sequences that encode SP and NKA are contained in exon3and exon6,respectively(Fig.1).The sequence that encodes NP g is contained in exons3,5and6and the sequence that encodes NPK is contained in exons34,5and6.Transcription of the PPT-A gene generates a pre-mRNA that could be spliced giving rise to four different mRNA isoforms(a,h,g and y) that differ in their exon combinations(Nawa et al.,1984;Kawaguchi et al.,1986;Krause et al.,1987; Harmar et al.,1990).h PPT-A mRNA contains all seven exons of the corresponding gene while a PPT-Table1
The human tachykinin peptide genes
Name Gene name Alternative name Accession number Chromosome location SP/NKA NPK/NP g TAC1PPT-A or PPT-I NM_013996(a isoform)7q21–q22
NM_003182(h isoform)
NM_013997(g isoform)
NM_013998(y isoform)
NKB TAC3PPT-B or PPT-II NM_01325112q13–q21
HK-1/EKA,EKB,EKC,EKD TAC4PPT-C NM_170685*17q21.33 *Provisional.
Fig.1.General process of synthesis of tachykinins from PPT-A,PPT-B and PPT-C genes in neurons.The figure shows the typical steps followed by any primary transcript representative of the tachykinin family,from transcription to translation and axonal transport.
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J.N.Pennefather et al./Life Sciences74(2004)1445–14631449 A mRNA lacks exon6,g PPT-A mRNA lacks exon4and y PPT-A lacks exon4and exon6(Fig.1).The SP precursor sequence is therefore synthesized from all four isoforms whereas the NKA sequence is present in h and g PPT-A mRNAs,the NP g sequence in g PPT-A mRNA and the NPK sequence is only encoded by the h PPT-A isoform.Translation of these mRNAs and posttranslational processing give rise to the different tachykinins(Nawa et al.,1984;Kawaguchi et al.,1986;Harmar et al.,1986,1990; MacDonald et al.,1988).
The alternative splicing of the PPT-A pre-mRNA affects regional distribution of SP and NKA.Hence, SP can be expressed alone while NKA expression is always accompanied by SP expression.Although there are few studies concerning the relative abundance of the different PPT-A mRNA isoforms in distinct tissues,it appears that the most abundant are g and h PPT-As,i.e.,the two mRNAs that encode both SP and NKA(Krause et al.,1987;Carter and Krause,1990;Lai et al.,1998;Pintado et al.,2003). This means that,in many occasions,SP and NKA will be synthesized and released as co-transmitters at both the central and peripheral levels(Takeda et al.,1990;Maggi,2000).
NKB is the only tachykinin derived from the preprotachykinin-B(PPT-B)gene(Table1)(Kotani et al.,1986;Page et al.,2000).The human gene consists of7exons,and the sequence that encodes NKB is located in exon5(Fig.1).
A new tachykinin encoded by a third preprotachykinin gene,PPT-C,has recently been identified (Zhang et al.,2000;Kurtz et al.,2002;Page et al.,2003).This tachykinin was first cloned in hematopoietic cells from mice and named hemokinin-1because of its important role in maturation of pre-
B to pro-B cells(Zhang et al.,2000).The PPT-
C gene has been subsequently cloned in rat and human(Kurtz et al.,2002;Page et al.,2003).The human gene consists of5exons,with the HK-1 coding sequence being located in exon2(Fig.1).The recent study by Page et al.(2003)has shown that transcription of the PPT-C gene can also generate four distinct mRNAs(a,h,g and y)as a result of the alternate splicing of the PPT-C primary transcript.This gives rise to four different peptides that have been named EKA,EKB,EKC and EKD.a PPT-C mRNA encodes a47amino acid,N-terminally extended form of human HK-1named EKA and a14amino acid tachykinin-like peptide named EKC(Table2).h PPT-C mRNA encodes a41amino acid,N-terminally extended form of human HK-1named EKB and a14amino acid tachykinin-like peptide named EKD(Table2).g and y PPT-C mRNAs encode only for EKB.
Table2
Amino acid sequences of mammalian tachykinins
Species Tachykinin Sequence
Mammals Substance P Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met.NH2 Mammals Neurokinin A His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met.NH2
Mammals Neurokinin B Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met.NH2
Rat/Mouse Hemokinin-1Arg-Ser-Arg-Thr-Arg-Gln-Phe-Tyr-Gly-Leu-Met.NH2
Human Hemokinin-1Thr-Gly-Lys-Ala-Ser-Gln-Phe-Phe-Gly-Leu-Met.NH2
Human Endokinin C Lys-Lys-Ala-Tyr-Gln-Leu-Glu-His-Thr-Phe-Gln-Gly-Leu-Leu.NH2 Human Endokinin D Val-Gly-Ala-Tyr-Gln-Leu-Glu-His-Thr-Phe-Gln-Gly-Leu-Leu.NH2 The three residues common to all tachykinins are shown in bold and italic.
The N-terminally extended forms of NKA(neuropeptide K and neuropeptide g)and of human HK-1(endokinins A and B)are not shown.
Tachykinin peptide synthesis
Translation of the mature mRNA from PPT-A,PPT-B or PPT-C generates a large polypeptide designated as prepropeptide that consists of a signal peptide,one or several copies of a neuropeptide and one or more spacer parts.The signal peptide,of approximately 16–30residues,is located at the N-terminal while the neuropeptide and spacers parts are randomly arranged,depending on the considered prepropeptide.The signal peptide allows the forming peptide to attach to and pass into the endoplasmic reticulum during synthesis and is then rapidly cleaved off,after polypeptide synthesis,to allow the formation of the propeptide.This one is transported to the Golgi apparatus where the spacer parts are split off from the final active peptide sequence at specific sites of single basic residues (Arg,Lys)or at two adjacent basic residues (Krause et al.,1987;Holmgren and Jensen,2001;Kurtz et al.,2002;Page et al.,2003).Fig.1shows a scheme of the process of synthesis of TKs in neurons.In this particular case,the active peptides are then packed in secretory granules budding off from the Golgi apparatus and transported through the axon to the nerve terminals (Krause et al.,1987;Holmgren and Jensen,2001).A consequence of this process of biosynthesis is that tachykinin mRNAs found in most peripheral tissues are probably located in non-neuronal cell types.
Tachykinin peptides
The primary structures of the actually known mammalian TKs are presented in Table 2.These closely related peptides are characterized by the presence of the common C-terminal,amino acid sequence Phe-X-Gly-Leu-Met-NH 2(Chang et al.,1971;Nawa et al.,1984;Tatemoto et al.,1985;Zhang et al.,2000;see Severini et al.,2002,for review).However,the recently discovered EKC and EKD possess a different C-terminal pentapeptide,Phe-X-Gly-Leu-Leu-NH2,a tachykinin-like motif that was previously unknown (Page et al.,2003)(Table 2).The primary structure of SP,NKA and NKB appears to be identical in all mammalian species.Conversely,the amino acid sequence of rat and mouse HK-1is different from that of the corresponding human peptide (Zhang et al.,2000;Kurtz et al.,2002;Page et al.,2003).The sequence assigned to human HK-1by Kurtz et al.(2002)is shown in Table 2and constitutes the C-terminus of the extended peptides EKA and EKB (Page et al.,2003).However,the primary structure of the active human peptide(s)is(are)still unknown.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 permits,on the basis of sequence identity,the search of new members of a family.Unfortunately,the structures of most of the genes encoding members of the tachykinin family are presently unknown.This,and the small size of the peptides,make the identification of new tachykinins in these genomes difficult.The recent discovery of HK-1and endokinins and the high
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J.N.Pennefather et al./Life Sciences74(2004)1445–14631451 number of TKs found in submammals suggest that the list of mammalian tachykinins could probably be increased in the following years(Jiang et al.,2003).
Human tachykinin receptors
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,NK2and NK3,have been cloned in different species including human(Table3)(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 structural organization and contain five exons,with introns interrupting the protein-coding sequence in identical positions(Fig.
2)(Hershey et al.,1991;Gerard et al.,1993;Krause et al.,1994).As a whole,the family of tachykinin receptors is one of the few,within the G protein-coupled receptors superfamily,that retains introns. Hence,while the majority of human genes contain introns,their presence is observed in less than10%of the G protein-coupled receptors genes(Minneman,2001).It has been hypothesized that the organization of exons may represents distinct functional and/or structural units and,in this context,the splice sites for the exons of mammalian TK receptors occur at the border of the sequences encoding the putative transmembrane domains(Hershey et al.,1991)(Figs.2and3).
Tachykinin receptor proteins
The three tachykinin receptors constitute a family of homologous receptors belonging to family1 (rhodopsin-like)of G protein-coupled receptors.This group of proteins includes a large number of membrane receptors which share the same structural motif:a bundle of seven hydrophobic transmem-brane domains(TM I-VII)with three extracellular loops(EL1,EL2and EL3),three intracellular loops (IL1,IL2and IL3),an extracellular amino-terminus and a cytoplasmic carboxy-terminus(Fig.3) (Regoli et al.,1994;Krause et al.,1994;Maggi,1995).The human tachykinin NK1and NK2receptors are proteins of407and398amino acids,respectively.The human tachykinin NK3receptor has465 residues and is longer than the NK1and the NK2receptors,being extended at the amino-terminal region. Considering the tachykinin receptor genes,exon1encodes the entire5V-untranslated region and the coding region through the end of TM III.Exon2contains IL2,TM IV and EL2.Exon3contains TM V Table3
The human tachykinin receptor genes
Receptor type Gene Accession number Chromosomal position NK1TACR1NM_0010582p13.1–p12
NK2TACR2NM_00105710q11–q21
NK3TACR3NM_0010594q25
and IL 3.Exon 4encodes for TM VI,EL 3and TM VII.Exon 5contains the cytoplasmic C-terminus and the entire 3V -untranslated region (Fig.3).
The three tachykinin receptors are recognized with moderate selectivity by endogenous tachykinins.SP,NKA and NKB act as full agonists on the three TK receptors although exhibit preferential binding to the NK 1,NK 2and NK 3receptor,respectively (Mussap et al.,1993;Regoli et al.,1994;Maggi,2000;Lecci and Maggi,2003).The rank order of potency for the NK 1receptor is SP z NKA >NKB;while it is NKA >NKB >SP for the NK 2receptor and NKB >NKA >SP for the NK 3receptor (Regoli et al.,1994;Maggi,2000).NP g and NPK preferentially bind to the NK 2receptor but also have high affinity for the NK 1receptor (Burcher et al.,1991;Van Giersbergen et al.,1992;Prat et al.,1994).Recent pharmacological studies have shown that mouse,rat and human HK-1,as well as EKA and EKB,produce effects almost identical to those of SP and act as NK 1receptor preferring agonists,although are also full agonists at tachykinin NK 2and NK 3receptors (Morteau et al.,2001;Bellucci et al.,2002;Camarda et al.,2002,Kurtz et al.,2002;Page et al.,2003).It has been suggested that endokinins A and B (or the active peptide they contain)could be the main endogenous ligands for the peripheral tachykinin NK 1receptor,particularly in non-innervated tissues (Page et al.,2003).
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 NK 1,NK 2and NK 3receptors.NKB shows different
functional
Fig.2.Schematic structure of the genes encoding the human tachykinin NK 1,NK 2and NK 3receptors.The protein-coding region of the genes is divided into five exons (I–V)interrupted by four introns (indicated by dashed lines).TM (1–7)indicates the transmembrane segments encoded by each exon and are shown by solid dark boxes.Amino acid positions at splicing sites are also indicated.
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effects when acting on the human NK 2receptor being as potent as NKA (human distal colon,Croci et al.,1998),or significantly less potent than NKA (human bronchi,Naline et al.,1989;human uterus,Patak et al.,2000b,2003).In addition,a recent report has shown that NKB induces oedema formation in the mouse lung and liver by a mechanism independent of the three known tachykinin receptors (Grant et al.,2002).Other studies have shown that SP is a poor activator of the NK 1receptor in the rabbit iris sphincter (Ueda et al.,1986;see Maggi,2000for a review).Several possibilities exist to explain the actual experimental data.
Existence of additional tachykinin receptors
In an effort to identify new tachykinin receptor genes,we searched the genome databases presently available by using BLAST (Altschul et al.,1997).The retrieved sequences were then subjected to phylogenetic analyses.Fig.4represents a neighbour-joining (NJ)tree (Saitou and Nei,1987)showing the evolutionary relationship between the tachykinin receptor types in different animal species.The wide distribution and high conservation of tachykinins and their receptors in organisms that diverge millions of years ago argue for an important physiological role of this system.Moreover,the nucleotide sequences are less conserved than the amino acid sequences,again indicating the existence of a selective pressure for conservation of these proteins.The phylogenetic tree,constructed from the amino acid sequences of tachykinin receptors,shows that they have a monophyletic origin i.e.,the three tachykinin receptors derive from a common gene.In vertebrates,there are three types of tachykinin receptors originated by duplications of one ancestral receptor already present in
the
Fig.3.Snake plot of the human NK 2receptor protein.Regions encoded by exons 1,3and 5are shown in grey and regions encoded by exons 2and 4are shown in white.The disposition of exons is identical in the NK 1and NK 3receptors.J.N.Pennefather et al./Life Sciences 74(2004)1445–14631453
Fig.4.Evolutionary relationships among amino acid sequences of tachykinin receptors,examined by means of a neighbour-joining (NJ)tree.The robustness of the branches is indicated by bootstrap values.Rat neuromedin B receptor and human FM3receptor are included as outgroups.Accession numbers of amino acid sequences are shown in brackets.Grey scale indicates separation among major different taxa.
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J.N.Pennefather et al./Life Sciences74(2004)1445–14631455 urochordate Ciona intestinalis(Sea squirt,Fig.4).It was observed that the recently characterized human NK4receptor or NK3B receptor type(Donaldson et al.,1996;Krause et al.,1997)is virtually identical to the sequence attributed to the guinea-pig NK3receptor(Page and Bell,2002;Pinto et al., 2002).The phylogenetic tree also shows that tachykinin NK1and NK3receptors clustered together and the tachykinin NK2receptor was separated from the NK1/NK3cluster in an earlier evolutionary period.The branches are supported by high bootstraps values(Felsenstein,1985)(Fig.4).Given that the complete human and mouse genomes are available(Lander et al.,2001;Venter et al.,2001; Waterston et al.,2002),the apparent presence of only one member of each type of tachykinin receptor in each mammalian species indicates that the presently known tachykinin receptors may constitute the complete family.However,the possible existence of additional tachykinin receptors,belonging to a different GPCR family or even to a different protein family cannot be excluded.In this context,it has been shown in bone marrow that SP is able to bind to distinct molecules that mimic the NK1receptor, such as fibronectin(Rameshwar et al.,2002)and the recently cloned hematopoietic growth factor inducible NK1receptor-type(Bandari et al.,2003a,b).
Existence of tachykinin NK1,NK2and NK3receptor isoforms
As mentioned above,a few members of the GPCR family retain introns in their genomic structures. Recent data suggest that,in these cases,the variety of GPCRs could be further expanded by the generation of splice variants that may play important roles in their localization,trafficking and signaling.Although the reasons explaining the presence of introns are not well understood,it seems probable that human G protein-coupled receptors genes that contain introns are under selective pressure to retain them,possibly reflecting important functional differences between isoforms (Minneman,2001).In the case of tachykinin receptor genes,an extensive search of the genome databases indicates that five is the lower number of exons present in any TK receptor throughout evolution and this is the number of exons found in mammalian receptors.In other metazoan species belonging to other groups,the exon number is higher,but the exon-intron boundaries present in mammals are also found in these species.
The presence of exons permits an expansion of the tachykinin receptor family and suggests a functional role for at least some of the splicing isoforms of these receptors,as each of them could show a distinct conformation and affinity for the different endogenous ligands.Several studies have indicated the existence of isoforms of the tachykinin NK1receptor,differing in the length of the C-terminal tail (Fong et al.,1992;Baker et al.,2003).The role of the short isoform and whether it is biologically active remains controversial.However,it has been shown that the long NK1receptor isoform is the most prevalent throughout the human brain,while the truncated form is the most represented in peripheral tissues(Caberlotto et al.,2003).A splice variant of the tachykinin NK2receptor has recently been identified in different human and rat tissues(Candenas et al.,2002)and there is little doubt that the list will be increased in the following years.
Existence of different conformations of tachykinin NK1,NK2and NK3receptors Recent evidence suggests that GPCRs could exist in a wide variety of conformations,each of which has a different ability to recognize ligands,to desensitize and to activate effector systems.These findings suggest a multistate model of GPCR activation,in which ligands stabilize unique and ligand-
specific GPCR conformations,thus enabling the receptor to activate one or more G proteins in a ligand-specific manner (Palanche et al.,2001;Lecat et al.,2002;Kenakin,2002;Gazi et al.,2003).The conformation adopted by the receptor may be conditioned by the ligand (Rosenkilde et al.,1994;Hastrup and Schwartz,1996)but may be also influenced by the microenvironement,i.e.,the extracellular medium and the phospholipidic composition of the membrane in the proximity of the receptor (Villar et al.,1998).The existence of different active conformations has been demonstrated for the NK 1receptor (Rosenkilde et al.,1994;Hastrup and Schwartz,1996;Maggi and Schwartz,1997)and the NK 2receptor (Palanche et al.,2001;Giolitti et al.,2002;Lecat et al.,2002).Each of these conformations shows a distinct affinity for different agonists and antagonists and is able to activate preferentially,at least in some cases,different effector systems (Palanche et al.,2001;Patacchini et al.,2001).
The existence of multiple induced conformations of the tachykinin receptors permits an understanding of the classical enigma of the existence of a ‘‘septide-sensitive’’NK 1receptor (Maggi and Schwartz,1997)and may also explain many of the unexpected responses and the species-related selectivity observed with selective tachykinin receptor agonists and antagonists in different tissues,even from the same species.
Alternative tachykinin receptor usage
As previously mentioned,the three known tachykinin receptors originate from duplication of a common ancestral gene.At this time,it is not possible to establish phylogenetic relationships for tachykinins and related peptides.However,several experimental data,such as the ability of SP to activate invertebrate tachykinin receptors,suggest that tachykinins and related peptides also originate from a common,ancestral gene (Nachman et al.,1999;Siviter et al.,2000).
Duplicated genes are common in genomes and the products encoded by these genes may have different functions but in many occasions,they share the same function (Holmgren and Jensen,2001).A recent,elegant study in yeast (Sacharomices cerevisiae )has shown that knocking out non-duplicated genes reduces fitness more severely than deleting one gene of a pair of duplicates (Gu et al.,2003).Duplication can therefore provide a basis not only for evolution and acquisition of new functions but also,and most important for an organism,for developmental stability and conservation of function.In other words,a main consequence of redundancy could be that the loss of function of a particular gene might not have noticeable effects due to functional substitution by the redundant gene(s).This could explain the results obtained with some knockout mice (for example,the fact that mice in which the oxytocin gene has been deleted develop normal labor,Nishimori et al.,1996)or even the poor results obtained with certain drugs (for example,tachykinin antagonists,see Lecci and Maggi,2003for review),when used for the treatment of human diseases.
The system of tachykinins and tachykinin receptors constitutes a typical example of duplication (Maggi,2000).First,all tachykinins can act as full agonists on the three known tachykinin receptors (Maggi and Schwartz,1997;Bellucci et al.,2002).Second,there are marked species-dependent differences in the pattern of expression of the tachykinin receptor types in a given tissue (Lecci and Maggi,2001;Pennefather et al.,1993;Candenas et al.,2001;Patak et al.,2002,2003),suggesting that different receptors can exert similar functions.This issue of duplication has been recently reviewed (Maggi,2000),showing examples of the different possibilities that exist following tachykinergic co-transmission:summation,cooperation or specialization.
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J.N.Pennefather et al./Life Sciences74(2004)1445–14631457 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 peptides,which appear to be important at both neuronal and non-neuronal levels.The wide distribution of tachykinins and tachykinin receptors and their participation in a great variety of inflammatory and immune diseases lead us to speculate that they can be involved in innate immunity.While the existence of more,unidentified tachykinin receptors cannot be excluded,most of the actual experimental data concerning tachykinins and their receptors can be explained by considering the existence of a wide variety of isoforms and conformers of the three known tachykinin receptors.
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