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Minireview: Diversity and Complexity of Signaling through Peptidergic G Protein-Coupled Receptors

Departments of Pharmacology (A.J.R., B.F.O’D., S.R.G.) and Medicine (S.R.G.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; and the Centre for Addiction and Mental Health (A.J.R., B.F.O’D., S.R.G.), Toronto, Ontario, Canada M5T 1R8

Address all correspondence and requests for reprints to: Susan R. George, Room 4358, Medical Science Building, 1 King’s College Circle, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: s.george{at}utoronto.ca.

Abstract

The transmission of signals by G protein-coupled receptors (GPCRs) that use peptides as ligands is critical for function of the gastrointestinal system. Molecular cloning has indicated that GPCRs constitute the most diverse transmembrane receptor family with many of these genes expressed in the gastrointestinal system. In addition to this molecular diversity, it has become clear that signaling through GPCRs is highly complex, with a wide variety of mechanisms that underlie different signaling responses and pathways through the same receptor. This minireview will summarize some of the emerging concepts of peptidergic GPCRs: signaling diversity including coupling to different G proteins, multiple endogenous ligands that can mediate different effects through binding to their cognate receptors, and homo- and hetero-oligomerization of receptors to enable cross talk or to produce novel signaling units.

THE COMPLEXITY OF intercellular signaling between and within physiological systems in higher organisms relies on an incredibly diverse array of cell-surface receptors and channels. Among these transmembrane molecules, G protein-coupled receptors (GPCRs) constitute the most diverse class with more than 1000 genes identified in the human genome. Upon activation by ligands (e.g. hormones, peptides, amino acids, ions), GPCRs can mediate a variety of intracellular responses via GTP-binding proteins (G proteins), such as regulation of ion channels, hormone secretion, enzyme activity, and gene expression. The classical view of GPCR signaling was initially one where a ligand binds to its cognate monomeric receptor at the cell surface to produce a highly specific chain of intracellular events via receptor coupling to a specific G protein. The complexity of GPCR signaling, therefore, was thought to be largely a function of the molecular diversity of receptor subtypes. However, research over the past decade has led to a growing awareness of additional mechanisms that can increase the repertoire of signaling pathways available to a GPCR. These include: the presence of multiple endogenous ligands that have different affinities for and which can exert differential effects on a particular receptor subtype; the ability of individual receptors to directly couple to different G protein isoforms; and oligomerization of GPCRs to enable cross talk between receptors or to produce novel signaling units (Fig. 1).

View larger version (20K): [in this window] [in a new window]   FIG. 1. Schematic of three mechanisms by which GPCR signaling diversity can be generated. A, Multiple endogenous ligands can have different affinities for their cognate receptors and can mediate distinct effects on receptor signal transduction, desensitization and internalization. Some ligands have been shown to be specific for particular receptor conformations that differentially couple to distinct G proteins. B, Oligomerization of GPCRs can confer unique pharmacological and functional profiles to a receptor, including affinity for specific peptide ligands and coupling to novel G proteins. C, Both homo- and hetero-oligomeric receptor complexes may have the ability to couple to more than one G protein, depending on their cellular environment, thereby conferring the ability to mediate different intracellular responses to the same ligand.

Molecular Diversity of pGPCRs

Multiple genes
At least 35 different families of pGPCRs and their ligands have been identified, with multiple receptor subtypes in most of these families each of which are encoded by separate genes (1). The majority of families can be grouped by sequence similarity within the broad classification scheme for GPCRs as Class A (rhodopsin like), whereas the rest can be placed into Class B (secretin/glucagon receptor-like). Class A receptors are distinguished by a set of highly conserved amino acids in the cytoplasmic half of the seven-transmembrane core that are required for receptor stability and for mediating the conformational changes that underlie receptor activation (2, 3, 4). Despite similar topology, Class B receptors share little amino acid sequence similarity with Class A receptors and are distinguished by a large extracellular amino-terminal domain that is critical for ligand binding and which contains six highly conserved cysteine residues that are likely involved in disulfide bond formation (5).

Typically, multiple subtypes exist within each family, ranging from two or three for cholecystokinin (CCK) receptors (CCK1-R, CCK2-R) and neurotensin receptors (NTR-1, -2, -3), four members of the glucagon receptor family (glucagon, glucagon-like peptide-1 and -2, and gastric inhibitory peptide receptors), five known members of the somatostatin receptor family (sstR1–5), six neuropeptide Y (NPY) receptors (Y1–Y6) and up to 18 chemokine receptors (CXCR1–6, CCR1–10, CX3CR1, XCR1). Receptors within each family are presumed to have similar binding domains specific for their cognate class of signaling peptides and, in many cases, activate common intracellular signaling pathways. However, as will be discussed below, receptors within each family have also been shown to differ in their relative affinity for ligands within a peptide family, G protein-coupling specificity, desensitization kinetics, and ability to associate with other GPCRs.

Alternative splicing
Although the molecular diversity of pGPCRs is generated primarily by the presence of multiple genes, splice variants for receptor subtypes have also been identified. The somatostatin receptor sstR2 gene can be alternatively spliced to give variants sstR2A and sstR2B that differ in their intracellular carboxyl-terminal domains (6). The functional distinction between the two sstR subtypes is not clear, although evidence suggests that the carboxyl-terminal truncated sstR2B isoform displays stronger coupling to adenylyl cyclase (7). A similar situation has been reported for type B endothelin receptor (ETR-B) splice isoforms (8, 9). Carboxyl-terminal splicing has also been described for the µ-opioid receptor (µOR), with at least 14 different variants identified. The reported differences between some of these µOR variants have been varying potencies of agonists (10) and differences in internalization and resensitization kinetics (11). Other than at the carboxyl terminus, splicing of a 37-amino acid fragment into the second extracellular loop of the calcitonin receptor (12) was demonstrated to reduce G protein-coupled signaling (13), and recently a transcript for the ETR-B has been identified that lacks exon 5, corresponding to the distal portion of extracellular loop 3 (14). Splicing out exon 5 of ETR-B may result in reduced protein stability and possibly attenuated G protein coupling to the receptor (14). Interestingly, the ETR-B/exon5(–) isoform can also undergo RNA editing at a single nucleotide in exon 4 (14), the significance of which is not known. Other GPCR splice variants have also been found, including a number of other calcitonin receptor variants, but these will not be discussed here.

Specificity of G Protein Coupling to pGPCRs

Specificity and multiplicity of G protein coupling
The specificity of G protein coupling to a given GPCR is typically defined in terms of the class of G subunit (G_s, G_i/o, G_q/11, G₁₂). Only more recently have there been reports describing more detailed molecular distinctions of the signaling complex, such as specific G subtype or the combination of G_ß and G subunit isoforms. Generally, Class A pGPCRs appear to couple primarily to either G_q/11 and/or G_i/o, which are commonly associated with activation of phospholipase C and inhibition of adenylyl cyclase, respectively. In contrast, Class B pGPCRs are primarily coupled to G_s and therefore mediate stimulation of adenylyl cyclase.

There are very few cases where the functional differences between pGPCR subtypes within a family can be defined primarily by the identity of the main associated G protein. One example is the melanin-concentrating hormone (MCH) receptor family, where MCH-R1 couples exclusively to G_i/o whereas MCH-R2 couples to G_q/11 (15). By comparison, the vast majority of pGPCRs within families appear to have overlapping G protein-coupling preferences. For instance, both orexin receptor subtypes couple to G_q/11 proteins, all three opioid receptors couple to G_i/o and all five functional NPY receptors have been shown to couple to G_i/o. A more nuanced distinction between receptor subtypes may exist, however, as has been suggested for members of the somatostatin receptor family, which all couple to G_i/o but which, under certain conditions, apparently display preferences for specific G_i subtypes (G_i1, G_i2 or G_i3) or G_o (16). Also, bombesin receptor subtypes, which display a common preference for G_q/11, differ in the efficacy of signaling when various G_ß and G subunit isoforms are heterologously expressed (17). The mechanism that underlies assembly of these highly specific complexes for each receptor and their functional significance remain to be elucidated.

Another way in which related pGPCRs that couple to the same G subunit may be functionally distinguished is their strength of coupling to the G protein. Both bradykinin receptor subtypes (B1 and B2) are known to couple to G_q/11, but the B1 receptor is more efficacious in ligand-dependent coupling when compared with B2 due to differences between the receptors in the carboxyl-terminal domain (18). Similarly, the angiotensin (AT)_II receptor displays weak coupling to G_q/11 and G_i/o (19, 20), unlike the AT_I receptor.

Many pGPCRs have been shown to couple to more than one G protein subtype (see Table 1 and Ref. 21 for review). Among Class A pGPCRs, the CCK-1 (22), neurokinin-1 (23), neurokinin-2 (24), and neurotensin-1 (25) receptors have all been reported to have the ability to couple to G_s proteins in heterologous cells in addition to G_q/11 and/or G_i/o. Other Class A receptors that display multiplicity of coupling include AT_I (G_q/11 and G_i/o) (26), CCK-2 (27), endothelin B (G_q/11 and G_i/o) (28), galanin R2 (G_q/11, G_i/o, G₁₂) (29), and vasopressin V1a (G_q/11 and G_i/o) (30). In Class B, calcitonin receptor-1a activation of phospholipase C and inhibition of adenylyl cyclase have been noted (31), suggesting coupling to G_q/11 and G_i/o. In addition, the glucagon receptor has been shown to couple to G_s and G_i/o (32) and both the glucagon-like peptide-1 receptor and the PTH receptor have been shown to be able to couple to G_i/o and G_q/11 along with G_s (33, 34).

Neurokinin receptors as a model for multiplicity of G protein coupling
The neurokinin receptor subtypes neurokinin 1 and 2 (NK1 and NK2) serve as excellent examples of a mechanism by which a pGPCR may couple to more than one G protein. Both receptors have been shown upon activation to elicit a biphasic response composed of a rise in both intracellular calcium and cAMP levels. For the NK1 receptor subtype, two high-affinity ligand-binding states exist in which the higher of the two corresponds to G_s coupling and the lower corresponds to G_q/11 coupling (23). For the NK2 receptor, the situation is reversed where a rapid calcium (and presumably G_q/11) response occurs in response to low levels of neurokinin A (NKA) and is followed by a cAMP (G_s) response that is amplified significantly when using higher concentrations of agonist (38). Interestingly, an endogenous truncated NKA peptide lacking the first three amino acids [NKA(4–10)] evokes only the calcium response and not the cAMP response through NK2 receptors (38). Also, the cAMP response can be eliminated by point mutations in the extracellular amino-terminal domain of the receptor (39). These latter two results suggest that different conformations of the receptor could underlie distinct activation states that have different ligand affinities, resulting in coupling to different G proteins. This effect is referred to as "agonist-specific trafficking" and has been described for a variety of pGPCRs and non-pGPCRS, the former including the bombesin receptor, µ- and -opioid receptors, and calcitonin receptor, among others (40).

Peptide Ligands for GPCRs

Multiple molecular mechanisms to generate biological diversity of peptide ligands
Endogenous peptide ligands for GPCRs are prototypically generated by enzymatic cleavage of a prepro-precursor to give fragments anywhere from 4–90 amino acids in length. Several biologically active peptides specific for one or more GPCRs within a family can be generated from a single precursor, such as somatostatin-14 and -28 from prepro-somatostatin (16, 41) and substance P, NKA, neuropeptide-K, and neuropeptide- from prepro-tachykinin A (42). Different processing enzymes can regulate which peptides are produced from the prohormone. For example, processing of the proglucagon gene by prohormone convertase 2 gives rise to glucagon in pancreatic A-cells, whereas glicentin, oxyntomodulin, and glucagon-like peptides-1 and -2 arise from the action of prohormone convertase 1/3 on proglucagon in the intestine and central nervous system (43, 44). Biologically active peptides can be further processed to give truncated peptides with divergent receptor specificity, as is the case for dipeptidyl peptidase-IV processing of NPY and peptide YY (PYY) to give truncated NPY(3–36) and PYY(3–36), respectively (45). NPY(3–36) and PYY(3–36) bind preferentially to the Y2 NPY receptor subtype (46, 47), unlike their precursors, which display equal affinity for both Y1 and Y2 receptors.

Different gene products can also encode peptides that activate similar receptors. Rat prepro-cortistatin is cleaved to produce cortistatin-14 and -29 (48), each of which are presumed to be additional ligands for somatostatin receptors. Similarly, prepro-tachykinin B encodes neurokinin B (49) and prepro-tachykinin C has recently been identified and shown to encode another ligand for tachykinin receptors, termed hemokinin-1 (50).

Additional mechanisms that have been shown to generate novel peptide ligands include alternative splicing, as has been described for the rat ghrelin gene to produce the isoforms ghrelin and des-Gln¹⁴-ghrelin (51), and processing of peptides or proteins that are already biologically active such as AT-converting enzyme-mediated cleavage of the Cterminal dipeptide motif from AT_I to produce AT_II (52). Also, xenin, a 25-amino acid peptide that can bind to the neurotensin-1 receptor, can be derived from aspartic protease cleavage of the amino terminus of the -cytosolic coat protein of the coatomer complex (53).

Posttranslational modification of amino acid residues in peptide ligands can regulate their potency or specificity and certain other modifications may be absolutely required for signaling. For peptides such as CCK, gastrin, NPY, orexins A and B, and the pro-opioid melanocortin-derived peptides, among others, C-terminal -amidation is required for function (54, 55, 56). Octanoylation of ghrelin at Ser³ is required for biological activity (51) and sulfation of Tyr⁷ or Ala⁷ in CCK and gastrin respectively is required for full potency of action on CCK1 receptors but not CCK2 receptors (56). Also, neuropeptide B, a ligand recently identified for the orphan GPCR GPR7, was shown to be brominated specifically at an N-terminal Trp residue (57), the significance of which is not yet known.

Specificity and multiplicity of peptide ligand-receptor interactions
For several families of pGPCRs, a common pattern of ligand selectivity appears to exist where one receptor subtype displays high affinity for only one specific ligand, whereas another subtype can bind numerous endogenous ligands with equally high affinity (see Table 2). The CCK1 receptor is selective for sulfated analogs of CCK but not gastrin, whereas the CCK2 receptor has high affinity for both sulfated and nonsulfated forms of CCK as well as gastrin (56). The endothelin-A receptor displays highest affinity for endothelin-1 (58), whereas the endothelin-B receptor displays equal affinity for the three known endothelin peptides (59). Similarly, orexin-A/hcrt1 receptors display preferential binding to orexin A, in contrast to orexin-B/hcrt2 receptors that can bind either orexin isoform with equal affinity (60).

The diversity of peptides available to activate a particular GPCR could allow a greater dynamic range of receptor responses while maintaining levels of specificity for specific endocrine and exocrine signals. The underlying assumption, of course, is that some or all of these ligands that bind with high affinity are physiologically available to the receptor in question. It will be important to determine not only what repertoire of ligand-receptor interactions occur in vivo, but also what the precise functional consequences of particular interactions are.

Functional distinctions between related peptide ligands
Several studies have highlighted potential functional differences between ligands that can act on the same receptor. Studies on the tachykinin receptors again serve as notable examples. As mentioned earlier, a naturally truncated isoform of NKA, NKA(4, 5, 6, 7, 8, 9, 10) has been shown to evoke an intracellular calcium response upon binding to the NK2 receptor, in contrast to full-length NKA, which elicits both calcium and cAMP responses (38). NKA can also elicit the same two signals by activating NK1 receptors (23). Interestingly, it has been demonstrated that NKA can only partially induce rapid desensitization of the NK1 receptor unlike the endogenous peptide agonists neuropeptide K and neuropeptide , which mediate significant levels of rapid receptor desensitization upon binding (64). Because neuropeptide K and neuropeptide are amino-terminal extensions of NKA, this result implicates the N-terminal residues of these peptides in mediating rapid receptor desensitization. Furthermore, it demonstrates that as for other peptides, the carboxyl-terminal region of peptide ligands contain the critical residues required for stimulation of receptor signaling.

Finally, a recent study on AT_I receptors has opened up the possibility of cooperativity between distinct ligands acting on the same receptor. AT_IV is a peptide derived from AT_II/III and binds with high affinity to AT_IV receptors, but not to AT_I receptors (AT_IR). Le et al. (65) have demonstrated that AT_IV can signal through a preactivated mutant of AT_IR, suggesting that AT_IV could activate the wild-type receptor after preactivation by AT_II or AT_III peptides. Although there is no biological evidence that this occurs in vivo, it is intriguing to consider the possibility that the action of different ligands from different cells could converge on a single receptor to serve as a signal for a physiological event occurring in both cells, in effect serving as a coincidence detection mechanism.

Oligomerization of pGPCRs

The concept that GPCRs exist only as monomeric entities in the plasma membrane has been radically altered over the past decade with direct biochemical evidence that a wide variety of GPCRs can form homo-oligomeric complexes and can hetero-oligomerize with other GPCRs or unrelated membrane proteins (see Table 3 and Ref. 67 for review). Techniques used to establish oligomerization of GPCRs have included Western blotting for dimers and other high molecular weight complexes, coimmunoprecipitation, dominantnegative and trans-complementation strategies, assays for bioluminescence or fluorescence resonance energy transfer (BRET, FRET) between two differently tagged receptors and atomic force microscopy. Although many lines of evidence suggest that dimers may be the basic functional oligomeric unit (66), they may exist as larger complexes that we will refer to below as oligomers.

In contrast to the aforementioned studies, a number of other studies using coimmunoprecipitation or FRET/BRET assays suggest that, for certain receptors, ligands can induce oligomerization (e.g. sstR5, B2, OR) (71, 75, 76) or dissociate pre-existing oligomers (74), implying that functional receptor monomers exist at the cell surface. However, as Terrillon and Bouvier have pointed out (85), an alternate explanation for these observations is that ligand-mediated changes in receptor conformation within an oligomer could result in modification of epitope recognition sites or shifts in orientation and relative distance between receptor fluorophores. This could change the efficiency of coimmunoprecipitation or FRET/BRET, respectively, without altering the oligomeric state of the receptors. It remains to be determined, therefore, whether constitutive homo-oligomerization is a process that occurs for all GPCRs. It is intriguing to speculate that oligomerization of GPCRs is an obligatory process for functional expression, as is the case for hetero-oligomerization of Class C GPCRs GABA_BR1 and GABA_BR2 (86), as well as for almost all other multitransmembrane receptors and ion channels.

Hetero-oligomerization of GPCRs
One of the most exciting developments in GPCR research over the past decade has been the demonstration that these proteins can hetero-oligomerize with other GPCRs of the same family, GPCRs from other families, and unrelated transmembrane proteins. In almost all of these cases, there has been a unique functional phenotype that has been conferred to the heteromer in the form of altered pharmacology, surface expression, desensitization or resensitization kinetics, or specificity of G protein coupling. This is highly significant in that it can increase the repertoire of signaling mechanisms available to a specific ligand. Furthermore, the unique profiles arising from hetero-oligomerization could explain some of the functional interactions observed in vivo between apparently unrelated receptors. For example, increased AT_I and B2 bradykinin receptor association in platelets and omental vessels has been noted in preeclampsic pregnant women (87), which results in a blunted physiological response to bradykinin and enhanced responsiveness to AT. Also, oligomerization of sstR5 with the D2 dopamine receptor was shown to increase the affinity of each receptor to its cognate ligand and enhance signaling (88), possibly accounting for previous observations of functional interactions between dopamine and somatostatin receptors in the brain (89).

Hetero-oligomerization between different members of the same family can profoundly affect cellular responses to agonists. Oligomerization of sstR1 with sstR5 (71), as well as sstR2A and sstR3 (70), resulted in complexes that showed greater internalization compared with individual receptors expressed alone. In addition, the sstR2A-sstR3 complex responded to agonists specific for sstR2 but not for sstR3, indicating that sstR2 was in effect a dominant-negative regulator of sstR3 function. An analogous situation has been described for AT_IIR attenuation of AT_IR activity (90). It is important to point out that sstR4 and sstR5 do not appear to oligomerize in heterologous cells (71), indicating a level of molecular specificity for the formation of complexes between sstRs.

Alterations in ligand affinity and/or signaling response as a function of intrafamily hetero-oligomerization have also been demonstrated for CCK, CCR chemokine, and opioid receptors. The CCK1R-CCK2R oligomer displays an enhanced response to CCK and a greatly diminished response to gastrin (73). Chemokine receptor oligomers composed of CCR2 and CCR5 have an enhanced response to specific agonists for either receptor and also display a novel calcium signal due to recruitment of G_q proteins to the heteromer (72). Opioid receptor complexes composed of the - and subtypes do not appear to have altered signaling properties, but show attenuated affinity for selective high-affinity ligands and increased affinity for partially selective ligands, along with reduced desensitization kinetics (79). Similarly, µ and opioid receptor heteromers show reduced affinity to ligands specific for each subtype, and there is evidence that the complex may couple to a novel, as yet unidentified, pertussis toxin-insensitive G protein (77).

Hetero-oligomerization with unrelated transmembrane proteins
GPCRs have been shown to oligomerize with unrelated transmembrane proteins such as ionotropic neurotransmitter receptors and receptor tyrosine kinases. For pGPCRs, an important series of studies have characterized interactions between calcitonin receptor-like receptor (CRLR) and a family of single transmembrane proteins known as RAMPs (receptor activity-modifying proteins). Oligomerization of CRLR with RAMP1 results in a complex that serves as a receptor for calcitonin gene-related peptide and oligomerization of CRLR with RAMP2 forms a functional receptor for the related ligand adrenomedullin (91). It was originally thought that differential glycosylation of the RAMPs mediated ligand specificity, but a number of subsequent studies have suggested otherwise (92, 93). It is possible that ligand specificity arises from RAMP forming part of the binding pocket with CRLR, or alternatively, particular RAMP subtypes inducing specific conformations of CRLR that differentially bind ligands.

Significance of GPCR hetero-oligomerization
It is apparent from all of the aforementioned examples that hetero-oligomerization can confer a remarkably diverse array of phenotypes to pGPCRs. As with reports describing the specificity of G protein coupling to pGPCRs, many oligomerization studies have identified and characterized GPCR interactions in heterologous systems. Ultimately, therefore, it is important to determine whether specific GPCR interactions actually occur in native tissues to begin to understand their physiological significance. Also of importance will be the delineation of mechanisms that underlie specificity of heteromeric assembly between GPCRs of the same family, of different families and between GPCRs and unrelated transmembrane proteins such as RAMPs.

Concluding Remarks

In this review, we have presented some of the mechanisms by which pGPCRs may mediate different responses to endogenous ligands (Fig. 1). Peptide signaling in the GI system is involved in the mediation of all aspects of GI function. Receptors that are involved in mediating these processes include those for somatostatin, CCK and gastrin, PP-fold peptides, neurokinins, opioids, and glucagon-like peptides. The complexity of GI function would suggest that these and other gut pGPCRs mediate diverse signals through some or all of the paradigms presented here.

Understanding how pGPCRs contribute to the function of physiological systems, as well as the interactions between these systems, is indeed a challenging task when considering the incredible molecular and functional complexity that underlies receptor signaling. Moreover, in this review we have not considered the roles for various intracellular proteins that have been shown to regulate almost all aspects of receptor function. These include the ß-arrestins and GPCR kinases, among others. Nevertheless, it is becoming apparent that certain basic principles and mechanisms of signaling diversity apply to all GPCRs, such as multiplicity of G protein coupling and receptor oligomerization, whereas other mechanisms such as multiplicity of ligands are characteristic of pGPCRs. Further examination of such signaling paradigms can ultimately be used to help determine how a single receptor or family of receptors could mediate specific physiological responses.

Footnotes

A.J.R. is supported by a Fellowship from the Centre for Addiction and Mental Health, and S.R.G. is a Canada Research Chair in Molecular Neuroscience.

Abbreviations: AT, Angiotensin; BRET, bioluminescence resonance energy transfer; CCK, cholecystokinin; CCR, receptors specific for chemokines containing Cys-Cys motif; CRLR, calcitonin receptor-like receptor; CXCR, receptors (R) specific for chemokines containing Cys-X-Cys motif; CX3CR, receptors specific for chemokines containing Cys-X-X-X-Cys motif; ETR, endothelin receptor; FRET, fluorescence resonance energy transfer; GI, gastrointestinal; GPCR, G proteincoupled receptor; MCH, melanin-concentrating hormone; NKA, neurokinin A; NK1 and NK2, neurokinin 1 and 2; NPY, neuropeptide Y; NTR, neurotensin receptors; µOR, µ-opioid receptor; pGPCRs, peptidergic GPCRs; PYY, peptide YY; RAMP, receptor activity-modifying protein; sstR1–5, five known members of the somatostatin receptor family; XCR, receptors specific for chemokines containing X-Cys motif.

Received January 19, 2004.

Accepted for publication February 18, 2004.

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