Cell signalling through thromboxane A 2 receptors

Cellular Signalling 16 (2004) 521 – 533 www.elsevier.com/locate/cellsig Review article Cell signalling through thromboxane A2 receptors Jin-Sheng Hu...
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Cellular Signalling 16 (2004) 521 – 533 www.elsevier.com/locate/cellsig

Review article

Cell signalling through thromboxane A2 receptors Jin-Sheng Huang, Santosh K. Ramamurthy, Xin Lin, Guy C. Le Breton * Department of Pharmacology, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Avenue (Mail Code 868), Chicago, IL 60612, USA Received 19 August 2003; accepted 6 October 2003

Abstract Thromboxane A2 receptors (TPs) are widely distributed among different organ systems and have been localized on both cell membranes and intracellular structures. Following the initial cloning of this receptor class from human placenta, the deduced amino acid sequence predicted seven-transmembrane spanning regions, four extracellular domains and four intracellular domains, making TP a member of the seven-transmembrane G-protein-coupled receptor (GPCR) super family. A single gene on chromosome 19p13.3 leads to the expression of two separate TP isoforms: TPa which is broadly expressed in numerous tissues, and a splice variant termed TPh which may have a more limited tissue distribution. Mutagenesis, photoaffinity labelling, and immunological studies have indicated that the ligand binding domains for this receptor may reside in both the transmembrane (TM) and extracellular regions of the receptor protein. In addition, separate studies have provided evidence that this receptor can couple to at least four separate G protein families. As a consequence, TP signalling has been shown to result in a broad range of cellular responses including phosphoinositide metabolism, calcium redistribution, cytoskeletal arrangement, integrin activation, kinase activation, and the subsequent nuclear signalling events involved in DNA synthesis, cell proliferation, cell survival and cell death. While activation of these different signalling cascades can all derive from TP stimulation, the relative signalling preference for a given cascade appears to be both tissue and cell specific. Finally, separate studies have indicated that TP signalling capacity can be both down-regulated by protein kinase activation and up-regulated by GPCR cross-signalling. Thus, the multitude of signalling events which derive from TP activation can themselves be modulated by endogenous cellular messengers. D 2003 Elsevier Inc. All rights reserved. Keywords: Thromboxane A2 receptors; Cell signalling; Platelets; Smooth muscle cells; Endothelial cells; Oligodendrocytes; Schwann cells

1. Introduction The initial purification and cloning of the thromboxane A2 receptor (TP) established this protein as a member of the super family of G-protein-coupled seven-transmembrane receptors [1]. The originally cloned TP from placenta (343 amino acids in length) is known as the a isoform, and the splice variant cloned from endothelium (with 407 amino acids) is termed the h isoform. Comparison of the two sequences reveals that even though the first 328 amino acids are the same for both isoforms [2– 4], the h isoform exhibits an extended C-terminal cytoplasmic domain. Furthermore, it is worth noting that expression of each protein is not equal within or across different cell types. Thus while platelets express high concentrations of the a isoform (and possess residual RNA for the h isoform), expression of the h isoform protein has not been documented in these cells.

* Corresponding author. Tel.: +1-312-996-4929; fax: +1-312-9964929. 0898-6568/$ - see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2003.10.008

Historically, TP involvement in blood platelet function has received the greatest attention. However, it is now clear that TPs exhibit a wide distribution in different cell types and among different organ systems (Table 1). For example, TPs have been localized in cardiovascular, reproductive, immune, pulmonary and neurological tissues, among others. Over the years, different biological roles for TP signalling have been established in both homeostatic and pathological processes (Table 2). Thus TP activation is thought to be involved in thrombosis/hemostasis, modulation of the immune response, acute myocardial infarction, inflammatory lung disease, hypertension, nephrotic disease, etc. Based on this consideration, attempts have been made to define the distinct signalling pathways by which TPs elicit their biological and pathological effects. In this regard, it is well documented that TPs have the capacity to activate a multitude of different signalling cascades which regulate cellular ion flux, cytoskeletal arrangement, cell adhesion, motility, nuclear transcription factors, proliferation, cell survival, and apoptosis. They are known to couple to at least four G proteins, which in turn activate numerous downstream

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Table 1 Thromboxane A2 Receptor Distribution Organ/Tissue [references] Spleen [8,9] Uterus [10] Placenta [14] Aorta [16] Intestine [10] Liver [10] Eye [18] Cells/Cell lines [references] Platelets [19 – 21] Glomerular mesangial cells [22] Oligodendrocytes [17,23] Cardiac myocytes [25] Epithelial cells [13,18] Hela cells [30] Smooth muscle cells [10] Kupffer cells [32] Human erythroleukemic megakaryocyte (HEL) [33] K562 (Human chronic myelogenous leukemia) cells [34]

Thymus [8 – 10] Kidney [9,11 – 13] Heart [15] Spinal cord [17] Brain [10,16] Lung [8,9]

Endothelial cells [2] Trophoblasts [10] Schwann cells [24] Astrocytes [26 – 28] Megakaryocytes [29] Hepatoblastoma HepG2 cells [10] Immature thymocytes [31] EL-4 (human T cell line) [9]

effectors, including second messenger systems such as inositol triphosphate (IP3)/DAG, cAMP, small G proteins (Ras, Rho), phosphoinositide-3(PI3) kinase, as well as protein kinase C (PKC) and protein kinase A (PKA). Furthermore, it has also become apparent that the signalling preferences between these different TP-mediated pathways vary in both a cell- and organ-specific manner. Consequently, TP activation in one cell type may lead to quite different signalling events than its activation in a separate cell type. This review discusses the process of ligand-induced TP activation, its signal transduction and its downstream effector activation in selected cells. For additional TP-related background information, several previously published reviews [5– 7] are recommended.

2. TP ligand interaction Much of the initial work to elucidate the ligand binding domain(s) of TPs centred on the participation of the transmembrane (TM) regions (Fig. 1). This is in large part due to earlier findings in bacteriorhodopsin and its GPCR homologue, rhodopsin, which revealed a binding pocket in the seventh spanning region of the receptor [51]. In addition, separate studies with a2- and h2-adrenergic receptors [52 – 54] indicated that the highly conserved TM7 region forms one critical segment of the ligand binding domain. On this basis, it was originally proposed that the binding domain may also reside in the TM7 region. In addition to participation of TM7, other investigations have suggested [55] coordination of the ligand head group with TM3 and interaction of the ligand alkyl chains with the TM4/TM5 regions. As a separate approach to define further the ligand coordination sites for TPs, various site-directed mutagenesis

studies have been performed. Specifically, Funk et al. [56] obtained four mutants with point mutations at TM7, i.e., between L291 and W299. Three of these mutants completely lost binding activity to both antagonists and agonists. In addition, Chiang et al. [57] reported that mutations of S201A and S255A in TM5 and TM6, respectively, caused altered affinity to the agonist, I-BOP, but had no effect on the antagonist, SQ29548 binding. Taken together, these latter results indicate that amino acid substitutions in either TM5, TM6 or TM7 regions can diminish ligand binding to TPs. Other mutagenesis studies [58] employing TP chimeras led the authors to conclude that residues in TM1 constitute an important portion of the TP binding site. Finally, reports from two different groups suggested that the putative disulfide bond between C105 and C183 in the first and second extracellular loops, respectively, plays a critical role in TPligand binding [57,59]. These groups also suggested that C102, which is conserved in most GPCRs, including the TP, also plays an important, yet unspecified role in ligand binding. Consequently, the previous results indicate multiple residues in TPs which may serve as potential ligand coordination sites, i.e., TM regions 1, 3 –7, as well as cysteine residues in the first and second extracellular loops (EL). ˚ ), it is However, since TP ligands are of limited size (c15 A unlikely that all of the suggested regions participate in ligand coordination. Rather, the reported loss of binding activity, in at least some of the previous mutagenesis studies, may derive from alterations in gross TP structure. Evidence has also accumulated that TP ligands can coordinate with extracellular domains. In particular, results obtained using a biotinylated TP antagonist SQB [60] suggested that the TP ligand coordination sites are not deeply embedded in a TM region, but must reside on the external aspect of the plasma membrane. Further evidence in support of ligand interaction at extracellular sites was provided in subsequent NMR studies which demonstrated that the TP antagonist SQ29548 produced a change in conformation of a constrained peptide containing amino acids representing the TP EL2 and EL3 regions [61,62]. Recently, a specific amino acid sequence contained within EL2 has been identified as a

Table 2 Biological roles/clinical links of TXA2/TP Hemostasis/thrombosis [35 – 37] Sickle cell disease [38] Cardiovascular disease [39] Lupus nephritis [40] Acute myocardial infarction [41] Nephrotic syndrome [42] Hypertension [43] Immune complex glomerulonephritis [44] Pregnancy-induced hypertension (PIH) [45] Asthma [46] Inflammatory lung diseases [47] Regulating acquired immunity [48] Chronic inflammation in atopic diseases [49] Chronic inflammatory bowel diseases [50]

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Fig. 1. Putative structures of the TPa and TPh receptor proteins.

critical participant in TP ligand binding [63]. Specifically, through the use of photoaffinity labelling techniques and sitedirected antibodies, it was established that TP residues C183 – D193 are essential for both ligand interaction and TP functional response. The importance of this region for TP ligand coordination was subsequently confirmed by studies of So et al. [64]. In these experiments, high resolution NMR of a TP EL2 peptide segment suggested ligand contact with V176, L185, T186 and L187. Furthermore, mutation of these residues (V176 to D, L or R; L185 and L187 to A, D or R; and T186 to A, R or S) led to a decrease in SQ29548 binding. The only exception was the V176L mutant which exhibited normal binding activity. In summary, while the precise location of ligand interaction with TP transmembrane regions remains to be more clearly defined, it appears that the C-terminal segment of the TP EL2 and possibly EL3 form critical coordination sites for this receptor protein. The existence of such a potential binding domain in EL2 is consistent with results obtained for both the bradykinin B1/B2 [65] and PGE [66,67] receptor classes.

3. TP signalling in platelets The heterotrimeric G proteins, consisting of a, h and g subunits, can be divided into four major families, Gq, G12, Gi and Gs [68 – 70], each of which contains various members. Previous studies have established that platelets possess all of the major G protein families and many of their

respective members. For example, antibody studies have shown platelet expression of Gq, G16 (Gq family), G12, G13 (G12 family), Gs, as well as Go, Gi and Gz (Gi family) [71 – 78]. While it has been shown that two of these families are involved in platelet TP signalling, i.e., Gq and G12, the relative contributions of these G proteins to the individual platelet functional responses is unclear. Nevertheless, definitive evidence has been provided that TP-mediated activation of selected G protein pathways leads to recruitment of numerous downstream effector targets. Probably the most well-characterized TP signal transduction pathway is through Gq which was the first G protein shown to couple functionally and physically to TPs [73,74]. Specifically, TP agonists have been shown to cause activation of the Gq heterotrimer and its subsequent dissociation into a and hg subunits. Even though the functional consequences of activated Gaq are uncertain, dissociated Ghg has been linked to activation of PLCh [79 – 83], recruitment of the phosphoinositide second messenger system [84,85], and the generation of diacylglycerol (DAG) [85,86]. The resulting IP3 then leads to intraplatelet calcium mobilization [84 –86] and the liberated DAG causes activation of protein kinase C (PKC) [85,87 –89]. What is less clear are the specific contributions of IP3 and DAG to the overall process of platelet activation. For example, the calcium ionophore A23187 is capable of eliciting the full range of platelet responses, i.e., shape change, aggregation and secretion [90 –92], suggesting that an increase in intracellular calcium is itself sufficient to cause activation of the signalling pathways involved in these events. On the other hand, DAG production has been asso-

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ciated with the process of the platelet secretion [93], and inhibition of PKC leads to a reduction in dense granule release [85,93 –95]. In addition, separate studies have provided evidence that Ghg activation of PI3 kinase [96 –98] is also involved in the platelet secretion response [99]. With these considerations in mind, it is most likely that each of these activation pathways contributes to the other, and that the overall platelet response is a composite of their individual contributing factors. When examining the complete response profile for TPmediated platelet activation, one must also take into account contributions from the G12/13 pathway. In this connection, it was initially demonstrated that activation of platelet TPs caused GTP binding to both Ga12 and Ga13, suggesting TP coupling to each of these Ga subunits. However, these studies also showed that the time course for photolabelling of Ga12 significantly lagged behind that of Ga13 and seemed to be inconsistent with the time course for the initial platelet activation response [71]. In confirmation of TP signalling through Ga13, a subsequent report demonstrated the direct physical and functional coupling of platelet TPs to the Ga13 subunit [78,100,101]. On the other hand, these experiments failed to show a similar physical association of platelet TPs with Ga12 subunit [78]. Taken together, the above findings suggest that platelet TP signalling through the G12/13 family may disproportionately proceed through G13, and that the TP-mediated activation of G12 occurs as a secondary rather than a primary event of TP signalling. A similar preference for G12 or G13 coupling has been described for other seven-transmembrane receptors, including the hydroxytryptamine receptor (5-HT4 receptor), the lysophosphatidic acid receptor (LPA) and the thrombin receptor (PAR), among others [102 – 104]. Regarding the downstream consequences of TP – G13-mediated signalling, evidence has been provided for Ga13 stimulation of the Rho/Rho kinase pathway and subsequent myosin light chain (MLC) phosphorylation in platelets [105,106]. Such events could lead to alterations in actin formation, platelet cytoskeletal rearrangement [107 – 110] and inside-out signalling [105,111– 113]. Aside from Gq and G12/13, evidence has also been provided that TPs can couple to Gi. In this case, however, controversy exists regarding whether such coupling occurs in human platelets. Thus, while Ushikubi et al. [114] showed that Gi2 functionally couples to TPs in phospholipid vesicles, and Gao et al. [115] reported TP – Gi signalling in ECV 304 cells (a human endothelial cancer cell line), separate studies have been unable to demonstrate such an association in platelets. For example, ligand affinity chromatography purification did not reveal the physical coupling of platelet TPs to Gi [74], and other experiments could not detect GTP labelling of Gi following TP stimulation [71]. Consequently, at present, there are no definitive results which establish direct TP coupling to Gi in platelets.

Mention should also be made of the potential ability of TPs to signal through other, less well-characterized, G proteins. In this regard, early work using immunoaffinity chromatography of platelet membranes revealed the presence of a high molecular weight protein (approximately 85 kDa) which co-purified with TPs in the column eluate [74]. This protein blotted with a Ga common antibody and became GTP labelled upon TP activation with U46619. Based on these findings, it was suggested [74] that TPs may functionally couple to a previously unidentified G protein. In subsequent studies, Vezza et al. [116] demonstrated TP signalling through a high molecular weight Ga subunit, i.e., Gh [117 –119]. It was shown that Gh (molecular weight 74 kDa) is present in platelets, couples to transfected TPs in COS-7 cells and is functionally linked to inositol phosphate formation [116]. While the above findings indicate that TPs may also signal through a G protein separate from Gq and G13, the consequences of such putative signalling are presently unknown. As indicated above, the linkage of specific TP – G protein signalling pathways to specific platelet activation events is not well defined. Nevertheless, several reports have indicated that certain of these events may be associated with selected pathways. For example, in Gqdeficient mice, the platelet aggregation response to U46619 is inhibited, indicating that TP-mediated aggregation requires signalling through the Gq pathways [120]. On the other hand, in these studies there appeared to be a divergence between TP-mediated platelet responses, since U46619-induced platelet shape change was still observed in Gq knockout mice [120]. This observation, coupled with the finding that TP-mediated shape change was blocked by the Rho-kinase inhibitor Y-27632, led to the conclusion that TP-induced shape change is a G12/13mediated event [105]. This suggestion would seem to be consistent with earlier observations that TP agonists can induce platelet shape change in the absence of measurable calcium mobilization [121] (which is presumably a Gq-mediated event). However, platelet shape change can be elicited by extremely low levels of TP activation, e.g., 2 –35 nM [121,122], and the presence of undetectable calcium fluxes at these low levels cannot be excluded. In addition, it would seem difficult simply to assign a single platelet response to a single G protein pathway, because platelet shape change can also result from Gq signalling. Thus, ADP is incapable of inducing shape change in Gq-deficient mouse platelets [120,123]. Since there is no definitive information demonstrating a direct coupling of platelet ADP receptors to G12/13, these findings suggest that the shape change response can be elicited by multiple signalling events. Consequently, under physiological signalling conditions, i.e., in the presence of intact Gq and G12/13 signalling, the TP-mediated shape change response may actually represent a composite of signalling through both of these pathways.

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Separate studies have linked TP – G12/13 signalling to the platelet aggregation response. Specifically, it was found that the Rho kinase inhibitor Y-27632 abolished TP-dependent shape change in Gq-deficient platelets, but had no significant influence on the aggregation response [113]. This finding led the authors to suggest that G12/13 can contribute to integrin activation by regulating a Rho kinase-independent mechanism. Furthermore, it was also shown that U46619-induced aggregation could occur in Gq-deficient mice if Gi signalling was simultaneously activated. Based on these findings, it was concluded that co-stimulation of G12/13 and Gi is sufficient to induce aIIb h3 activation. Similar conclusions were reached by a subsequent study from another group [124]. In these experiments, attempts were made to eliminate the participation of Gq signalling in the TP response by using a low concentration of U46619 which is presumably selective for the TP –G12/13 pathway. Under these conditions, simultaneous activation of Gi signalling resulted in platelet aggregation at a concentration of U46619 which itself could not induce the aggregation response. Finally, TP-mediated G protein signalling is known to result in the activation of numerous of downstream kinases as part of the platelet response. Thus, TP stimulation has been associated with activation of Ras [125], Rho [105,126], Rac [126] and related effectors such as p160ROCK, as well as the Ca/calmodulin system [127]. Other studies have demonstrated TP-mediated activation of pp72(syk), pp60(c-src) tyrosine kinase and mitogen-activated protein kinase (MAPK)(p38MAPK, p42MAPK) [105,128 – 133]. Since, however, the process of platelet activation leads to multiple feedback signalling mechanisms, it has been difficult to determine whether the stimulation of a specific kinase serves as an initiating event, or an event which results as a consequence of the overall platelet response. Nevertheless, recent work by Li et al. [99] suggests that PI3 kinase is linked to the process of TPmediated platelet secretion. In these studies it was shown that U46619 causes PI3 kinase-dependent phosphorylation of Akt, and that platelets deficient in PI3 kinase exhibit an impaired U46619-induced second wave of secretion. However, in this case as well, it is not clear whether the PI3 kinase-dependent secretion derives from downstream events associated with the TP-mediated signalling process or by direct activation via Ghg. Clearly, additional studies will be required to define more fully the precise TP signalling events linked to the activation of different platelet kinases and the functional consequences of such activation. In summary, platelet TPs have the capacity to couple functionally to different G protein families and elicit a multitude of downstream signalling events. While it appears that activation of certain of these pathways can be associated with selected platelet responses, it seems likely that in the fully functional platelet, each of these pathways contributes to the overall shape change, aggregation and secretion response.

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4. TP signalling in other cells and tissues 4.1. Smooth muscle cells Since its initial identification as the ‘‘rabbit aorta contracting substance (RCS)’’, TXA2-mediated contraction has been examined in many smooth muscle types including vascular, respiratory, uterine and intestinal [134 – 140]. While not completely understood, certain results have provided evidence that the signalling pathway of TXA2induced contraction appears to involve activation of the small GTPase Rho, Rho kinase, myosin light chain kinase, and to a lesser extent PKC [141,142]. On the other hand, another study using canine pulmonary vascular smooth muscle found that an inhibitors of tyrosine kinases (genistein) and Rho kinase (Y-27632) abolished U46619-induced contraction, whereas PKC (calphostin C), p38 MAPK (SB203580) and MAPK kinase (PD-98059) inhibitors were ineffective [143]. Most recently, U46619-induced contraction was studied in isolated rat mesenteric resistance arteries [144]. In this case, however, a tyrosine kinase inhibitor (tyrphostin A25) was ineffective in blocking contraction, but both PKC inhibitors (GF109203X) and p38 MAPK inhibitors (SB-203580) were found to block the contraction response. Based on these findings, it therefore appears that TXA2-induced contraction involves activation of different signalling mechanisms depending on both the species and the type of smooth muscle being investigated. Aside from its role in stimulating smooth muscle contraction, TP activation has been shown to have mitogenic effects. For example, using rat vascular smooth muscle, it was found that TP agonists increased thymidine incorporation and proliferation by stimulating cell cycle progression from the S to G2/M phase [145,146]. Similarly, work by Morinelli et al. [147] showed that TP stimulation in guinea pig coronary artery smooth muscle produced increased DNA synthesis, activation of the ERK1/2 MAPKs, and the S6 kinase p85RSK. Further work in rat aortic smooth muscle cells [148] provided evidence that stable TP agonists induced the expression of c-fos and early growth response gene-1 (egr-1) mRNA. These studies also revealed that TP activation potentiated the mitogenic effects of platelet derived growth factor (PDGF). In contrast, separate results have indicated that even though TP stimulation of rat aortic smooth muscle increases proto-oncogene expression and accelerates protein synthesis, it does so in the absence of DNA synthesis or cell proliferation [149,150]. Specifically, in these experiments the results indicated that TXA2 stimulates smooth muscle hypertrophy by increasing the synthesis and release of endogenous basic fibroblast growth factor (bFGF). Other work has also demonstrated that rat aortic smooth muscle proliferation induced by angiotensin II or tumour necrosis factor alpha (TNFa) is mediated by a MAPK-dependent induction of cyclooxgenase 2 (COX-2) and increased TXA2 production [151].

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Additional experiments have investigated the TP signalling pathways mediating the mitogenic response in human uterine vascular smooth muscle cells. In this connection, Miggin and Kinsella [152] showed that TP stimulation not only caused the activation of ERKs but also caused the activation of c-Jun N-terminal kinases (JNKs). This response was found to be dependent on PKC, PKA, PI3kinase, and appeared to be linked to transactivation of the epidermal growth factor (EGF) receptor. More recently, Gallet et al. [153] showed that TP-mediated ERK activation involves both pertussis toxin-sensitive and -insensitive G proteins, src kinase, as well as transactivation of matrix metalloproteinases. In short, previous studies have provided evidence that TP activation not only causes smooth muscle cell contraction, but also initiates a host of nuclear signalling events. These studies also reveal apparent differences in the nuclear signalling profile for TP-mediated responses, and while the reasons for these disparities are unknown, they may at least in part relate to species differences and/or experimental culture conditions. 4.2. Endothelial cells Following the cloning of the placental TP receptor, a second splice variant with a divergent cytoplasmic tail was cloned from a human endothelial cell library [2]. However, even though it was determined that endothelial cells express this splice variant termed TPh as well as the platelet/ placenta variant TPa, the specific roles of these variants in endothelial cell function remain unclear. Nevertheless, various studies have made significant contributions to defining endothelial cell TP signalling. Ishizuka et al. [154] determined that activated human vascular endothelial cells express intracellular adhesion molecule-1 (ICAM-1) following the production and release of endogenous TXA2, and that this TP-dependent expression of ICAM-1 is PKC-dependent. In addition, the surface expression of other adhesion proteins, i.e., vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule (ELAM-1), were also induced by TP stimulation in a PKC-dependent manner [155]. On the other hand, there appear to be differences in the downstream signalling events associated with the TP-mediated expression of these adhesive molecules. Thus, ICAM-1 or ELAM-1 expression was found to be dependent on activation of the NFnB and AP-1 transcription factors, whereas VCAM-1 was found only to involve NFnB activity. Separate evidence has been provided that endothelial cell TPs are linked to the processes of cell migration, survival, angiogenesis and tumour metastasis. Specifically, it was found that TX2 produced via COX-2 is a mediator of human microvascular endothelial cell migration (HMVEC) and angiogenesis [156] Similarly, other studies reported that TXA2 synthesis and release is associated with the migration of human umbilical vein endothelial cells (HUVECs) or HMVECs in response to bFGF or vascular endothelial

growth factor (VEGF) [157]. However, these findings appear to be in contrast to those reported by a separate group [158] who found that TP stimulation inhibited human endothelial cell migration and in vitro capillary formation. Additional work by this group provided evidence that TP signalling through both TP variants induces apoptosis of endothelial cells and inhibits the phosphorylation of Akt kinase which is involved in cell survival [159]. Furthermore, there also appeared to be a divergence in the signalling pathways by which these events occurred, since activation of adenylyl cyclase and PKA caused inhibition of apoptosis induced by the TPh isoform, but did not block apoptosis induced by TPa activation. Most recently, this group examined the interaction between TXA2 and TNFa signalling as it may occur under inflammatory or ischemic conditions [160]. It was found that TP agonists stimulated the expression of leukocyte adhesion molecule (LAM) on endothelial cells via TPh. In contrast, TP signalling had the opposite effect in the presence of TNFa, in that TP activation was found to reduce TNF-mediated LAM expression and enhance endothelial cell apoptosis. This effect was ascribed to a reduction in the prosurvival NFnB activation pathway induced by TNFa. Consequently, TP activation appears to recruit a number of endothelial cell responses ranging from the expression of surface adhesive molecules involved in cell migration, angiogenesis and tumour metastasis to the induction of apoptosis in inflammatory conditions. 4.3. CNS and PNS cell types More recently, evidence has been provided that TPs foster both physiological and pathological responses in the CNS and PNS. For example, CNS TPs contribute to the angiotensin II-mediated dipsogenic response [161], the stimulation of foetal adrenocorticotropic hormone (ACTH) secretion [162], the central adrenomedullary outflow, and adrenaline release [163]. In addition, TXA2 has been shown to elevate blood pressure by multiple mechanisms including activation of specific CNS and PNS TPs as well as interaction with vascular smooth muscle TPs leading to vasoconstriction in the systemic circulation [162,164,165]. Aside from hormonal or cardiovascular effects which may impact homeostasis, TPs also appear to contribute to pathological conditions such as cerebral ischemia – reperfusion injury. This effect may be due to several considerations including an increase in the generation of oxygen radicals [166], local vasoconstriction and/or platelet deposition [167 –171]. A similar involvement of TPs has been linked to secondary damage following spinal cord injury [172,173], as shown by the finding that TP antagonists provide protective effects on spinal cord perfusion following experimental cord injury [174]. While the cellular function of TP signalling in neurons has not been extensively studied, several potentially important features of this pathway have been identified. For example, hippocampal TPs seem to play a functional role in both neuronal excitability and synaptic transmission.

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Thus, it was found in rat CA1 neurons that TP activation dose-dependently suppressed whole-cell Ca2 + currents [175]. Additionally, other studies reported that activation of presynaptic TPs increased the release of glutamate, while activation of postsynaptic TPs was associated with inhibition of synaptic transmission [176]. Both of these effects were found to be mediated by a PKC-dependent pathway which was both pertussis- and cholera toxin-insensitive. The first indication of the presence of TP signalling in glial tissue was the observation that a TXA2 analogue, STA2 (9,11-epithio-11,12-methano-thromboxane A2), stimulates phospholipase C and inositol phosphate accumulation in 1321N1 human astrocytoma cells via a pertussis toxininsensitive G protein [177]. Using radioligand binding, it was subsequently demonstrated that TPs exist on primary cultured rabbit astrocytes, and that activation of TPs also results in phosphoinositide hydrolysis [26]. Furthermore, using immunoaffinity chromatography purification, this group later showed that 1321N1 cells expressed two TPs (MW 58 and 55 kDa), which copurified with both Gq/11 and G12 proteins [178]. Additional studies provided evidence that differentiation of 1321N1 cells by dibutyryl-cAMP was accompanied by a reduction in TPR density and phosphoinositide mobilization in response to agonist stimulation [179]. On the other hand, the differentiated cells revealed a marked STA2-mediated activation of the MAPK cascade via stimulation of a phosphatidylcholine-specific phospholipase C and PKC [180]. Collectively, these results therefore suggest a possible shift in TP signalling pathways upon cell differentiation. In separate experiments with antibodies against specific TP sequences, it was noted that TPs are concentrated in discrete rat brain regions. Thus, unlike the diffuse labelling pattern which would be expected from astrocytes, the labelling was distinctly associated with myelin-enriched white matter structures, e.g., the striatum, the internal capsule and the optic tract [16]. These observations therefore provided the first indication that TPs are highly concentrated in myelinated regions of the CNS, and suggested the presence of TPs on oligodendrocytes. This notion was further supported by RT-PCR analysis which revealed the presence of TP mRNA in brain glial cells including oligodendrocytes [28,181]. Subsequent studies established that cultured OLGs (or their tumour-related cell line, human oligodendroglioma [HOG] cells) express TPs on their plasma membranes, and that this protein has an apparent molecular weight and ligand affinity comparable to that seen in platelet membranes [17,23] or 1321N1 human astrocytoma cells. These studies also revealed that activation of OLG TPs by U46619 elicited intracellular Ca2 + mobilization, which is consistent with earlier observations linking Gq/11 signalling to TPs in astrocytes [27]. Finally, recent data has linked TP signalling in OLG cell lines to functional effects, i.e., enhanced proliferation and survival [182]. While the signalling pathways associated with these effects are unknown, it appears that TP stimulation leads to

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activation of the MAPK cascade and associated nuclear signalling events. In particular, activation with low nanomolar concentrations of U46619 causes ERK1/2 and CREB phosphorylation, up-regulation of c-fos and p-65, as well as stimulation of AP1 and NFnB [182]. In addition to their presence on OLGs, TPs have been identified in other myelinating cells as well. Thus, initial studies revealed dense immunostaining of white matter in the rat spinal cord [17], and subsequent experiments demonstrated immunocytochemical and immunoblot labelling of TPs in rat Schwann cells (rSC) [24]. Interestingly, these rSC TPs were not only localized on the plasma membrane but were also associated with the cytoplasm and the nucleus. Functional analysis of these TPs revealed that unlike OLGs, U46619 stimulation of rSC cells did not cause measurable Ca2 + release, but did result in a marked increase in both cAMP levels and CREB phosphorylation [24]. Taken together, the above studies provide evidence for the presence of functional TPs in both the CNS and PNS, and even though the precise TP signalling mechanisms in these organ systems remain to be established, it appears that TP activation can modulate both neuronal and glial cell responses through cytoplasmic and/or nuclear signalling events. 4.4. Other cell types Aside from the organ systems described above, TPs are also known to be functionally involved in the immune system. In this regard, Namba et al. [8] cloned the mouse TP and examined its expression in various tissues by Northern blot analysis. Of the mouse tissues examined, the thymus appeared to possess the highest expression of TPs, followed by the spleen and lung. In later studies, it was determined that the receptor density in immature thymocytes is comparable to that found in platelets, and that TP stimulation mediates apoptosis and DNA fragmentation of CD4+/CD8+ cells [31]. Recently, this group has generated TP-deficient mice to study the consequences of TXA2 signalling in the immune system [50]. It was found that TXA2 produced by dendritic cells (DC) induces the chemokinesis of naive T cells, impairs DC –T cell adhesion, and inhibits DC-dependent proliferation of T cells. These results therefore suggest that TP signalling modulates acquired immunity by interfering with DC – T cell interaction. Finally, other studies have provided evidence that kidney TPs may play a role in both normal and pathological conditions [22,40,42,44,183,184]. Specifically, cloning of the rat kidney TP revealed the presence of TP mRNA in various regions of the kidney [11]. The widespread distribution of kidney TPs was later confirmed by immunological studies which demonstrated TP receptor protein immunoreactivity along the lumen of glomerular capillary loops, as well as in mesangial cells, podocytes, and epithelial cells [13]. Additional experiments have shown that TP stimulation of mesangial cells increases cell contraction, promotes cell

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proliferation, causes changes in cellular ion fluxes, mobilizes phosphoinositides, activates PKC, and increases fibronectin, laminin, collagen, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) mRNA levels and transforming growth factor synthesis. [22,185 –187]. More recently, separate studies have [188] determined that TP stimulation has a cytoprotective role in renal epithelial cells via the activation of the NFnB and AP-1 transcription factors. In summary, the above results suggest that TXA2 may have unique roles in kidney function, and that these roles are dependent upon its particular site of action.

platelet cAMP levels with PGI2 caused a substantial phosphorylation of TP-associated Ga13 [100]. This phosphorylation was shown to be PKA-dependent [100] and to occur at a single site within the functionally important Switch I Region of the Ga13 subunit, i.e., at Thr203 [101]. These findings were consistent with an earlier report demonstrating that cAMP blocks U46619-induced Rho/Rac activation [126] in platelets, and suggest that signalling through the TP pathway may itself be modulated by activation of second messenger kinases.

6. Modulation of TP signalling by other GPCRs 5. Modulation of TP signalling by protein kinases: PKC, PKA, PKG Early investigations into modulation of TP signalling by cyclic nucleotides revealed that elevation of platelet cAMP levels caused a suppression of U46619-induced intraplatelet calcium mobilization. This effect was interpreted as evidence for one potential mechanism by which cAMP may inhibit TPmediated blood platelet activation [90,189,190], i.e., enhanced calcium sequestration through PKA-mediated phosphorylation of a 22-kDa protein [191 – 196]. Once the primary structure of TPs was resolved, it became apparent that TPs possess one PKA/PKG phosphorylation site and four PKC phosphorylation sites. Based on this consideration, experiments were next undertaken to determine whether TPs can serve as substrates for PKC, PKA and/or PKG. The initial studies in this area revealed that PKC and PKA caused phosphorylation of a fusion protein spanning the latter third extracellular loop of TPs [197], leading the authors to suggest that PMA or cAMP (PKC and PKA, respectively) may desensitize TP-induced platelet activation through phosphorylation of TPs themselves. While a subsequent report using transfected HEK293 cells questioned physiological significance of this effect [198], a later study [4] concluded that PKC-mediated receptor phosphorylation may in fact serve as one mechanism for TP desensitization in platelets. Regarding the modulatory effects of cGMP, a separate group used immunoaffinity chromatography to demonstrate that PKG has the capacity to phosphorylate TPs [199], in a putative G protein coupling domain. On this basis, it was postulated that such phosphorylation may interfere with TP – G protein signal transduction. Consistent with this suggestion was the finding that cGMP-mediated phosphorylation was associated with decreased U46619-stimulated GTPase activity. Even though a net decrease in GTPase activity cannot differentiate between effects on the receptor and/or its associated G protein, these results nevertheless provided a link between PKG phosphorylation and inhibition of the TP –G protein signalling transduction mechanism. As a separate approach to investigating cyclic nucleotide modulation of TP signalling, other studies have examined the possible phosphorylation of TP-coupled G proteins. In particular, these experiments demonstrated that elevation of

Even though different GPCRs are known to function through distinct signal transduction pathways, it is also apparent that there are certain points along the activation cascade by which these pathways communicate. Thus, agonist – GPCR interaction can influence the cellular response to a separate agonist interacting with a different GPCR. One example of such ‘‘cross-talk’’ between pathways is the phenomenon of synergism. Although synergism is widely observed in pharmacological therapeutics, the molecular mechanisms leading to such disproportionate responses have not been extensively studied. However, there is increasing evidence to suggest that communication between GPCRs can occur through different mechanisms including heterodimerization [200 – 206], cross-reactions among GPCR downstream effectors [207] and G protein redistribution [208 –212]. While the processes of heterodimerization or downstream effector cross-signalling have not been defined for TPmediated responses, recent evidence suggests that signalling between TPs and other GPCRs can occur through agonistinduced redistribution of G proteins. In this regard, initial studies focused on the classical synergism which occurs between platelet PAR1 receptors and TPs. It was found that low-dose activation of PAR1 receptors led to a substantial increase in ligand binding to TPs [208]. Furthermore, this increased ligand binding was associated with a shift in the Hill coefficient from a single- to a two-site model, and the appearance of a high affinity TP pool [209]. Additional experiments also demonstrated that platelet PAR1 receptor activation causes a measurable increase in TP-associated Gaq. Based on these findings, a model (Fig. 2) was developed to describe a dynamic equilibrium that may exist between TPs and other GPCRs which couple to the same Ga subunits. In this model, both TPs and PAR1 receptors exist in at least two different ligand affinity states: uncoupled low-affinity and G-protein-coupled high affinity. Upon agonist binding to the high ligand affinity PAR1 receptors, the Gahg heterotrimer dissociates and interacts with downstream effectors. During reassociation, these Ga subunits may or may not recouple to their original GPCR receptor classes. Rather, the mass and affinity TP and PAR1 for the ‘‘free’’ Ga will determine the final equilibrium of the

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above, recent studies [113,124] demonstrated that co-stimulation of TP-mediated G12/13 and P2Y12 (or a2A-adrenergic)-mediated G i signalling led to platelet integrin activation. These results are consistent with previous studies which demonstrated synergistic interactions between U46619 and ADP [215 – 217] or between U46619 and epinephrine [217,218]. While the mechanism of this crosssignalling between TP- and Gi-coupled receptors is unknown, it is tempting to speculate that it may proceed through similar mechanism of hg redistribution as the bradykinin (B2) and P2Y receptors described above. Alternatively, this synergism may derive from hg activation of downstream effector sites. Clearly, these concepts are at a relatively early stage of development, and additional studies will be required to define further the various mechanisms by which TPs have the capacity to cross-signal and the possible physiological consequences of these events. Fig. 2. Dynamic equilibrium between TPs and other GPCRs.

7. Summary reassociation process. In the case of PAR1 receptor activation, both the PAR1 mass and its Ga affinity would decrease because of PAR1 internalization and because of PAR1 – ligand interaction. Acting together, these effects would foster increased Ga coupling to TPs and their consequent shift to a higher ligand affinity state. Thus, it appears that there can be a cycling of G proteins not only within a specific receptor class but also between receptors that share common Ga (or possibly hg) subunits. This process of mass/affinity-directed TP – G protein coupling also suggests that a competition can exist between TPs and other GPCRs, and that this competition may define the predominant signalling pathways through which TPs signal under different experimental conditions and in different cell types. For example, even though TPs signal through the Gq, G12/13 pathway or Gi pathways in most cells, TP-mediated Gs signalling has been shown to be a significant pathway in transfected COS-7 cells [213,214] and rat Schwann cells [24]. On the other hand, there is no direct evidence for TP cross-signalling through a redistribution of hg G protein subunits. Nevertheless, previous results have indicated that this process can occur for other GPCRs [210]. In these experiments, two receptor groups were studied: the adenosine A(1)/a2C adrenergic receptors which couple to Gai and the bradykinin B(2) or P2Y (UTP-responding) receptors which couple to Gaq. It was found that activation of Gaicoupled receptors increased the potency and the efficacy of inositol phosphate production induced by bradykinin or UTP activation. Furthermore, the overexpression of Gh1g2 also resulted in increased potency and efficacy of bradykinin or UTP, and that almost all possible combinations of Gh(1– 3) with Gg(2– 7)produced similar effects. On this basis, the authors proposed that Ghg subunits could redistribute from an activated Gai-coupled receptor to an activated Gaq-coupled receptor and enhance the receptorstimulated GDP/GTP exchange of Gq [210]. As mentioned

Over the years, it has become increasingly apparent that TPs are involved in a multitude of physiological and pathological processes. They are present on a variety of cell types and have been localized to both plasma membrane and cytosolic compartments. As a member of the seventransmembrane receptor class, TPs are known to couple to and signal through several different G protein families. As a consequence, these receptors have been shown to participate in the activation of a number of different signalling cascades. Even though many of the details regarding these signalling events are presently unknown, certain characteristics are apparent. For example, TP signalling preference among these different pathways is not uniform across all cell types, or in certain circumstances, even within a given cell type. Thus, blood platelet TP activation does not result in elevated cAMP levels, whereas such activation does produce measurable cAMP increases in PNS Schwann cells. Furthermore, TP signalling produces apoptosis in certain cell types and prolonged survival in others. This difference in signalling preference also seems to extend to different stages of the cell cycle where its activation of various nuclear transcription events changes during proliferation and differentiation. Consequently, it would seem that caution should be exercised when attempting to define the signalling pathways of this eicosanoid receptor. The accumulation of data thus far compiled across different cell lines establishes the signalling capacity of TPs and not necessarily that which occurs in a given cell at a particular stage of its development.

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