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Journal of Molecular Endocrinology (2009) 42 361-370    DOI: 10.1677/JME-08-0162
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Review

The clinical–molecular interface of somatostatin, dopamine and their receptors in pituitary pathophysiology

 Diego Ferone, Federico Gatto, Marica Arvigo, Eugenia Resmini, Mara Boschetti, Claudia Teti, Daniela Esposito and Francesco Minuto

Department of Endocrinological & Medical Sciences (DiSEM) and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV, 6, 16132 Genova, Italy

(Correspondence should be addressed to D Ferone; Email: ferone{at}unige.it)


   Abstract
Top
 Abstract
Introduction
 Heterogeneity of somatostatin...
 Functional role of somatostatin...
 The emerging concept of...
 Declaration of interest
 Funding
 References
 
The role of somatostatin and dopamine receptors as molecular targets for the treatment of patients with pituitary adenomas is well established. Indeed, dopamine and somatostatin receptor agonists are considered milestones for the medical therapy of these tumours. However, in recent years, the knowledge of the expression of subtypes of somatostatin and dopamine receptors in pituitary adenomas, as well as of the coexpression of both types of receptors in tumour cells, has increased considerably. Moreover, recent insights suggest a functional interface of dopamine and somatostatin receptors, when coexpressed in the same cells. This interaction has been suggested to occur via dimerisation of these G-protein-coupled receptors. In addition, there was renewed interest around the concept of cell specificity in response to ligand-induced receptor activation. New experimental drugs, including novel somatostatin analogues, binding to multiple somatostatin receptor subtypes, as well as hybrid somatostatin–dopamine compounds have been generated, and recently a completely novel class of molecules has been developed. These advances have opened new perspectives for the medical treatment of patients with pituitary tumours poorly responsive to the present clinically available drugs, and perhaps also for the treatment of other categories of neuroendocrine tumours. The aim of the present review is to summarise the novel insights in somatostatin and dopamine receptor pathophysiology, and to bring these new insights into perspective for the future strategies in the medical treatment of patients with pituitary adenomas.


   Introduction
Top
 Abstract
 Introduction
Heterogeneity of somatostatin...
 Functional role of somatostatin...
 The emerging concept of...
 Declaration of interest
 Funding
 References
 
Somatostatin (SRIF) and dopamine (DA) are two critical regulators of pituitary cells function, being involved in the negative control of hormonal secretion of the anterior pituitary (Ben-Jonathan & Hnasko 2001, Guillemin 2005). The actions of SRIF and DA are mediated by specific G-protein-coupled receptors (GPCR) that are present on the cells of both the normal gland and of the pituitary adenomas: SRIF receptor (SSR) subtypes 1, 2, 3 and 5 (sst1–5; Miller et al. 1995, Hofland & Lamberts 2001); and the subtype 2 (D2) of DA receptors (DR; Missale et al. 1998). Conversely, the expression of sst4 is rather infrequent, whereas D4 receptor has also been found expressed in the anterior pituitary and in a small subset of pituitary tumours (Missale et al. 1998, Pivonello et al. 2004b); however, its role in the pathophysiology of the pituitary has not been examined yet. Two different isoforms of sst2 and D2 have also been found and characterised: the two forms of the sst2 (sst2A and sst2B) and of D2, the long (D2long) and short (D2short) isoforms, are generated via alternative splicing (Missale et al. 1998, Hofland & Lamberts 2003). While sst2B is almost unexpressed in humans, the two D2 isoforms may be coexpressed and associated with different intracellular signalling transduction mechanisms, and may, therefore, elicit different effects after binding with DA agonists (Missale et al. 1998).

As for the physiological lineaments, SRIF, interacting with SSRs, inhibits the secretion of a wide range of hormones, including the pituitary GH, PRL and TSH. Signalling through SSRs is multifaceted. Indeed, binding of SRIF or SRIF analogues to SSRs initiates a complex set of signalling events triggered by the interaction of the activated receptors with a large number of different protein partners, involving firstly specific G-protein activation (Moller et al. 2003). As a consequence, the activities of several key enzymes, including adenylyl cyclase, phosphotyrosine phosphatases (PTPases) and mitogen-activated protein kinase (MAPK) are modulated along with changes in the intracellular levels of calcium and potassium ions (Florio 2008). G proteins, via the stimulation of PTPases, may also produce some of the cytostatic actions of SRIF (Fig. 1A). For example, in pituitary tumour cells, SRIF analogues produce their anti-proliferative action by acting on the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway (Theodoropoulou et al. 2006). Whereas, more recently, apoptosis has been also observed upon binding of SRIF and SRIF analogues to sst3, and possibly to sst2 as well. (Fig. 1A). Which type of signalling prevails in given cells depends on the cell-specific distribution of SSR subtypes and signalling elements, as well as on SSRs internalisation, desensitisation and/or receptor crosstalk (Lahlou et al. 2004, Schonbrunn 2008). Finally, the subcellular expression pattern of SSR subtypes and their activity in response to agonist treatment may also be affected by intracellular complements, such as proteins involved in intracellular vesicle trafficking (e.g. β-arrestin). Indeed, different SRIF analogues may induce distinct conformations of the receptor/ligand complex, preferentially coupled to either receptor signalling or receptor endocytosis (Tulipano & Schulz 2007).


Figure 1
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  		Figure 1 (A) Principal intracellular signalling cascades associated to somatostatin receptors in pituitary cells. Somatostatin (or somatostatin analogues) binding to somatostatin receptors inhibits adenylyl cyclase, activates K channels and/or inhibits Ca channels. Phosphotyrosine phosphatases and mitogen-activated protein kinase are modulated as well and along the stimulation of phosphotyrosine phosphatase, may also produce cytostatic actions. More recently, increase in apoptosis via p53 has been shown as well. Most of these effects are mediated by G proteins. (B) Principal signal transduction associated with the activation of dopamine receptors in pituitary cells. Dopamine (or dopamine agonists) binding to pituitary D2 receptors inhibits adenylyl cyclase, phosphatidylinositol metabolism, activates voltage-activated potassium channels and decreases voltage-activated L-type and T-type calcium currents, modulates the activity of phospholipase C, activates the mitogen-activated protein kinase and extracellular signal-regulated kinase pathway. The expression of POU1F1 transcription factor is inhibited by activation of D2 receptors, exerting a negative control on PRL gene expression. Most of these effects are mediated by G proteins. AC, adenylyl cyclase; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase 3β; MAPK, mitogen-activated protein kinase; G{alpha}, Gβ and G{gamma}, G-protein subunit; PDPK1, 3-phosphoinositide-dependent protein kinase 1; pHi, intracellular pH; PLC, phospholipase C; PKA, protein kinase A; PTPase, phosphotyrosine phosphatase.

 
The D2 receptor is important for mediating the effects of DA to control movement, certain aspects of behaviour in the brain and PRL secretion from the anterior pituitary. Multiple transduction mechanisms are activated by D2 receptors in the pituitary. In addition to inhibition of adenylyl cyclase, pituitary D2 receptors inhibit PI metabolism, stimulate voltage-activated potassium channels and decrease voltage-activated L-type and T-type calcium currents (Fig. 1B). All these effects are mediated by G proteins (Missale et al. 1998). Studies on D2 gene expression in different types of pituitary adenomas showed a variable D2 expression localised in the cytoplasm and nuclei of a large number of adenomas. However, the significance of nuclear localisation of D2 remains unclear (Ferone et al. 2007a). Moreover, both isoforms of D2 receptor are relevant to the signalling pathways involved in the proliferation and cell death of pituitary tumour cells, possibly through p38 MAPK and ERK activation (Ferone et al. 2007a).

Along the last decades, the knowledge on the pathophysiology of these two families of GPCRs in the pituitary has progressively increased due to the synthesis and availability of specific subtypes receptor agonists and antagonists, useful not only in experimental settings, but also of incredible value in clinical practice as potent therapeutic agents. However, until recently, each receptor molecule was believed to interact separately with G proteins, while a series of observations have challenged this conclusion. Indeed, the emerging concept that these GPCRs may also function as homo- and heterodimers has opened a complete new scenario for those trying to interpret confusing results obtained in vivo or in isolated tissues that do not seem to obey the classical binding and activation patterns described for individual cloned receptors.

The clinical–molecular interface of SRIF, DA and their receptors in pituitary pathophysiology will be discussed in this review, because it represents an ideal model of the possibility of a whole new level of complex interactions that could multiply the range of activities of the already large family of GPCRs.


   Heterogeneity of somatostatin and D2 dopamine receptor distribution in pituitary adenomas
Top
 Abstract
 Introduction
 Heterogeneity of somatostatin...
Functional role of somatostatin...
 The emerging concept of...
 Declaration of interest
 Funding
 References
 
Both SSRs and D2 receptors are significantly expressed in pituitary adenomas, even if there is a large interstudy variability reflecting not only the different sensitivity of the techniques employed, but also the compelling heterogeneity of these tumours (Stefaneanu et al. 2001, Moller et al. 2003, Saveanu et al. 2008).

In most GH adenomas, sst2, sst5 and D2 coexpression has been found, at both mRNA and protein levels, however, half of GH tumours also coexpress sst3 and sst1, particularly mixed GH/PRL adenomas (Panetta & Patel 1995, Stefaneanu et al. 2001, Zatelli et al. 2005, Taboada et al. 2007, Ferone et al. 2008, Saveanu et al. 2008). The vast majority of prolactinomas express high number of D2 receptor; however, sst1, and particularly sst5, are also notably present, while sst2 is only expressed in a minority of them (Miller et al. 1995, Panetta & Patel 1995, Stefaneanu et al. 2001, Fusco et al. 2007, Saveanu & Jaquet 2008). Non-functioning pituitary adenomas (NFPAs), including gonadotrophinomas, as well as {alpha}-subunit producing tumours, express mainly sst3 and, at a lesser degree, sst2, seldom associated with sst1 (Zatelli et al. 2004, Taboada et al. 2007). The D2 receptor is expressed in most clinically NFPAs, and, interestingly, heterogeneous D2 isoform expression has been demonstrated in these tumours, in which D2short seems more favourable than D2long expression for both in vitro and in vivo growth inhibitory response to DA agonists (Renner et al. 1998, Pivonello et al. 2004b, Taboada et al. 2007). In Cushing's disease, corticotroph adenomas mainly express sst5 and D2 receptors, whereas sst2 is expressed at lower levels together with sst1 and sst3 (Stefaneanu et al. 2001, Pivonello et al. 2004a, Batista et al. 2006, de Bruin et al. 2009). Both sst5 and D2 receptors seem to play an important role in the regulation of ACTH release, at least in a subset of specific pituitary area-derived corticotroph tumours (Pivonello et al. 2004a, de Bruin et al. 2009). Interestingly, SSRs and D2 receptor seem differentially regulated by glucocorticoids in neuroendocrine cells (de Bruin et al. 2008a). This aspect should be taken into account because cortisol-lowering therapy could indirectly affect the responsiveness of tumour's cells to drugs targeting these receptors. Moreover, recently, it has been proposed that canine corticotroph adenomas may provide a model to study corticotroph cell pathophysiology (de Bruin et al. 2008b). However, since distinct differences do exist between human and canine corticotroph adenomas in terms of SSR and D2 receptor expression and regulation, as well as the relative responses to SRIF and DA agonists, these differences should be carefully considered when using dogs as a model to evaluate efficacy of novel SRIF and DA agonists in human Cushing's disease (de Bruin et al. 2008b). D2 receptors have been found at very low density and with a different distribution of the two isoforms in the rare TSH-secreting tumours as well, where, on the contrary, sst1, and especially sst2 and sst5, are significantly represented (Panetta & Patel 1995, Stefaneanu et al. 2001, Yoshihara et al. 2007, Saveanu et al. 2008).

Although the above-mentioned high variability may be due in part to the different techniques used in these studies (mainly mRNA analysis by northern blot, in situ hybridisation and real-time PCR, or protein assays, such as radioactive-binding studies, and, more recently, immunohistochemistry), an apparently rather complex situation came out because of the great heterogeneity of these tumours.

However, when we examine more deeply these data, a reliable pattern apparently emerges. The D2 receptor is the GRCP mostly represented in the pituitary tumours, and is overall associated with two or more SSR subtypes in the different adenoma categories, possible following preferential outline in certain subclasses: sst2 and sst5 are linked with D2 in the majority of somatotroph tumours, D2 is coexpressed with sst1 and sst5 in prolactinomas, and with sst3 and sst2 in NFPAs, finally D2 and sst5 are almost equally represented in corticotroph tumours (Zatelli et al. 2005, de Bruin et al. 2009, Ferone et al. 2008, Saveanu et al. 2008; Fig. 2).


Figure 2
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  		Figure 2 Distribution of somatostatin and D2 dopamine receptors in the different type of pituitary adenomas. The D2 is the receptor mostly represented in the pituitary tumours and is preferentially associated with sst2 and sst5 in somatotroph tumours, with sst1 and sst5 in prolactinomas, with sst3 and sst2 in clinically non-functioning adenomas and with sst5 in corticotroph tumours. In mixed and plurihormonal adenomas, a highly heterogeneous pattern is observed.

 

   Functional role of somatostatin and D2 dopamine receptors in pituitary adenomas and implications for therapeutic strategies
Top
 Abstract
 Introduction
 Heterogeneity of somatostatin...
 Functional role of somatostatin...
The emerging concept of...
 Declaration of interest
 Funding
 References
 
It is, however, intriguing that the observations arising from studies of characterisation of the receptor profile in pituitary tumours did not always correlate with the efficacy expected for the corresponding medical therapy.

In fact, while dopaminergic drugs are efficient in more than 90% of prolactinomas (Gillam et al. 2006), SRIF analogues, octreotide and lanreotide control about 80% of TSH-secreting adenomas (Beck-Peccoz & Persani 2002, Ness-Abramof et al. 2007), but only 60% of GH-producing tumours (Freda 2002, Burt & Ho 2006). Moreover, clinically available SRIF analogues or DA agonists have a minor role in the medical treatment of NFPAs, since they have been shown to control the growth of less than 20% of this tumour type (Colao et al. 2008). However, it has been also shown that DA agonist therapy is associated with a decreased prevalence of residual tumour enlargement in patients with NFPA, particularly when treatment is instituted before tumour remnant growth is detected (Greenman 2007). On the other hand, although still in lower percentage compared with other pituitary adenomas, at least cabergoline, a D2-selective second-generation DA agonist, seems able to control a specific subset of corticotroph pituitary tumours (Pivonello et al. 2004a, de Bruin et al. 2009). Similarly, a new SRIF agonist, pasireotide, displaying a broader receptor-binding profile compared with octreotide and lanreotide, appears promising for the medical treatment of Cushing's disease (Ben-Shlomo & Melmed 2007).

The item becomes even more interesting when we are faced with the plurihormonal adenomas of the acidophilic cell line, namely the pure somatotroph, somatomammotroph tumours, the truly mixed GH/PRL adenomas and even the very rare stem cell tumour (Asa et al. 1992). This assorted family represents the 30% of pituitary tumours in acromegaly. The plurihormonal adenomas have been shown to be functionally different, displaying a different sensitivity to the treatment with SRIF and/or DA agonists, also when administered in combination. Indeed, although the target cell could contribute to drug sensitivity, again in this case the specific receptor distribution on tumour cells plays the major role in determining the sensitivity to both SRIF and DA analogues (Ferone et al. 2001). In fact, it has been recently demonstrated that the really mixed GH/PRL tumours seem more resistant to SRIF analogues, whereas almost no difference in sensitivity, not only to SRIF analogues but also to DA agonists, has been observed in somatotroph and somatomammotroph adenomas (Ferone et al. 2008). This seems to be mainly due to the lower density of sst2 in mixed tumours. However, an interfering role of other receptor subtypes cannot be ruled out. Indeed, previously, in an experimental model, a full concordance between tumour response to the DA agonist bromocriptine and the expression of D2 receptors by tumour cells was found in five lineages of a spontaneous transplantable rat pituitary tumour (SMtTW) exhibiting different PRL/GH phenotypes (Trouillas et al. 1999). This model resembles the various tumour phenotypes encountered in human pituitary pathology. However, Zatelli et al. (2005) elegantly investigated the in vitro response of a heterogeneous group of human somatotroph adenomas to experimental SRIF analogues. The authors suggested that adenomas expressing D2 are less likely to respond to SRIF analogues in terms of inhibition of GH secretion (Zatelli et al. 2005).

The modern view of the concept of resistance to medical therapy must take into account the effect on tumour mass as well. Indeed, until a few years ago, in secreting adenomas, the responsiveness or resistance to the medical therapy was defined according to the hormonal response. In general, the cases biochemically responsive were those experiencing also significant tumour size reduction during long-term treatments. However, at least for somatotroph adenomas treated with SRIF analogues, it is becoming clear that many adenomas may undergo impressive tumour shrinkage, although the hormonal hyperproduction is not fully controlled (Bevan 2005, Casarini et al. 2006, Cozzi et al. 2006, Resmini et al. 2007).

To overcome the resistance to single-agent treatment, the use of a combined SRIF analogue and DA agonist treatment schedule has been explored, particularly in GH-secreting adenomas, which are known to be potentially responsive to both classes of compounds (Colao et al. 2007). More recently, NFPAs were shown to be sensitive to a combined treatment as well, however, the response rate seems limited (Colao et al. 2007). No study with combined therapy has been reported in PRL- and ACTH-secreting adenomas so far, and no rationale exists today for such an approach with the presently available compounds (Table 1).


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  		Table 1 Principal studies reporting results of combined treatment with dopaminergic agents and somatostatin analogues in pituitary adenomas

 

   The emerging concept of somatostatin and D2 dopamine receptors dimerisation in pituitary adenomas: implications for pharmacology and drug discovery
Top
 Abstract
 Introduction
 Heterogeneity of somatostatin...
 Functional role of somatostatin...
 The emerging concept of...
Declaration of interest
 Funding
 References
 
The experience of combination therapy has paved the way for new studies that have provided the first evidence for a new challenge in the field of receptor pathophysiology and therapeutic strategies. Indeed, the discrepancy between the ‘presence’ of a given profile of SSR/D2 and the limited efficacy of agonist drugs may be partially explained by the crosstalk on the cell membranes, or even at post-membrane level, of the GPCRs (Ferone et al. 2007b, Saveanu & Jaquet 2008). The preclinical use of new experimental compounds is crucial for understanding the new picture. In fact, SSR distinct profiles may correspond to different responses to SRIF subtypes preferential ligands. For example, the sst5 preferential ligand, BIM-23268, suppresses PRL secretion in prolactinomas, as well as ACTH secretion in corticotroph tumours (Saveanu & Jaquet 2008). The relationship between SSR expression and their functionality may be more complex in GH-secreting adenomas expressing low levels of sst2, where the sst2-preferential ligand octreotide is ineffective in suppressing GH release. In such cases, an sst5 selective agonist may be of value because this SSR subtype is often highly expressed (Saveanu et al. 2001). However, in this specific setting, a bi-specific analogue, such as BIM-23244, which can activate both receptors, could achieve a better control of GH hypersecretion (Saveanu et al. 2001). Moreover, a selective sst1 ligand, BIM-23926, has been shown to inhibit in vitro hormone secretion and cell viability in GH- and PRL-secreting adenomas and in a subset of NFPAs (Zatelli et al. 2003, 2004). Whereas in corticotroph adenomas, the predominant mRNA expression of sst5 over sst2 makes these adenomas highly sensitive to multireceptor ligands, such as the new SRIF analogue pasireotide (de Bruin et al. 2009). Recent data have showed that pasireotide modulates SSR trafficking in a manner clearly distinct from other SRIF analogues, providing an alternative explanation for the differential regulation of SSR responsiveness during long-term administration of stable SRIF analogues (Lesche et al. 2008). Moreover, SSRs act not just as monomers but may display a differential tendency to homo- and heterodimerise, depending on the subtype involved, and perhaps also on the cell type in which they are expressed (Durán-Prado et al. 2008). Indeed, pairs of distinct SSRs, such as sst2–sst3 and sst1–sst5, may interact and establish a physical interaction, resulting in altered pharmacological or/and functional properties (Durán-Prado et al. 2008). In this view, while the first chemical approach, following the discovery of the five SSRs, was to construct ligands with a high affinity for each subtype, more recently the pharmaceutical companies have driven the research toward new compounds interacting with more than one SSR subtype. Moreover, knowing the association of SSRs and D2 receptor in the majority of pituitary adenomas, another chemical approach consisted in the synthesis of chimeric molecules containing structural elements of both SRIF and DA and directed against both the superfamilies of GPCRs (Ferone et al. 2007a,b, Saveanu & Jaquet 2008). The first molecules of this class, BIM-23A387 and BIM-23A760, were characterised by their sst2 and D2 and sst2, sst5 and D2 affinity respectively, and resulted effective in controlling hormone hypersecretion in vitro in somatotroph adenomas that were partial responders to octreotide (Saveanu et al. 2006). These chimeric compounds were effective at lower concentrations compared with analogues directed toward a single receptor, and were even more efficient than octreotide in combination with cabergoline (Saveanu et al. 2006).

In addition to the binding properties of the hybrid compounds, other mechanisms may explain their greater efficiency in suppressing hormone release: the pharmacokinetics characteristics, the longer stability and, very intriguing, the demonstrated capacity in transfected cell lines, in which SRIF and DA ligands could induce or maintain receptor homo- and heterodimerisation and increase functional activity (Rocheville et al. 2000). This latter observation suggests that at least a portion of the high activity of these chimeric molecules may be due to promoting the formation of dimers between GPCRs.

Presently, the experience with the so-called ‘dopastatin’ molecules has been extended to the NFPAs as well (Gruszka et al. 2006, Ferone et al. 2007b, Florio et al. 2008). Although in vitro chimeric agonists were effective in inhibiting {alpha}-subunit secretion (Ferone et al. 2007b) as well as cell proliferation (Florio et al. 2008) in this heterogeneous class of pituitary tumours, the results appear less convincing so far. From a certain point of view, it seems that also the chimeric molecules may act differently in various tissues tested, and the effect could differ according to cell types. Actually, this hypothesis was already explored with SSR subtype-specific analogues. In fact, another in vitro study on NFPAs, while revealing the potential importance of sst1 in mediating an inhibitory effect of a selective agonist on chromogranin A and {alpha}-subunit secretion as well as on cell viability, also demonstrated that the incubation of these cells with a sst5-selective agonist may enhance pituitary cell viability (Zatelli et al. 2004). Therefore, it seems that the coexpression of SRIF and D2 receptors is not sufficient to improve the responsiveness of pituitary tumours to the anti-secretory and/or the anti-proliferative actions of the new class of hybrid compounds, indicating that once again the cell type should also be taken into account. In support of this hypothesis is the experience in testing these drugs with other cell systems than pituitary cells. For example, dopastatins resulted more effective in inhibiting cell growth in a non-small lung carcinoma cell line compared with subtype-specific SSR analogues and DA agonists, demonstrating in this cell system, constitutively expressing SSRs and DRs, a clear additivity of the hybrid compounds (Ferone et al. 2005). Conversely, in gastric enterochromaffin-like cell, the dopastatin BIM-27A760 did not displayed an additive effect on histamine secretion and cell proliferation (Kidd et al. 2007). On the other hand, the activation of multiple SSRs by pasireotide significantly reduced cell proliferation in the neuroendocrine tumour cell line NCI-H727 (Ono et al. 2007), and inhibited cell growth and catecholamine secretion in cell cultures of phaeochromocytoma, also inducing apoptosis (Pasquali et al. 2008). Indeed, a differential cytotoxicity of chimeric compounds was recently observed in bronchopulmonary and small intestinal neuroendocrine tumour cell lines (Kidd et al. 2008). The responses of each individual cell line suggested that neuroendocrine tumours from diverse locations arising from different neuroendocrine cells may require cell-specific anti-proliferative agents based on the unique receptor profile of individual lesions (Kidd et al. 2008). Pituitary and ectopic corticotroph tumours, expressing sst2, sst5 and D2 receptors, are promising potential target for dopastatin molecules. In fact, although up to now no data have been issued in this field, pre-clinical results and single preliminary clinical experiences encouraged the research in this group (Pivonello et al. 2005, de Bruin et al. 2009), while in prolactinomas, where sst5 and D2 are coexpressed, only a slight additivity of specific agonists was demonstrated in cell cultures (Saveanu & Jaquet 2008).

Finally, GPCR dimerisation seems to influence not only pituitary cell functions, but may also provide a mechanism for the lack of tolerance seen with currently available SRIF analogues and their ability in controlling pituitary tumour growth. Indeed, heterodimerisation between sst2 and sst5 has been recently found involved in this important phenomenon (Grant et al. 2008). The next important step will be the accurate characterisation of the post-receptor signalling pathways, which certainly depend on the SRIF and DR profile; however, it could be significantly affected by the specific neuroendocrine (and non-neuroendocrine) cell type (Fig. 3).


Figure 3
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  		Figure 3 Somatostatin/dopamine chimera-induced dimerisation of somatostatin and dopamine receptors. Potential intracellular signal transduction pathways linked to the heterodimer. Receptor activation may result in phosphorylation of c-Jun N-terminal kinase that up-regulates P21WAF1/CIP1, while inhibiting transcription of the cyclin, KI67. This combination results in growth arrest of neuroendocrine cells. However, depending on the hybrid receptor complex, P21WAF1/CIP1 transcription can also be decreased (adapted from Kidd et al. 2008). JNK, c-Jun N-terminal kinase.

 
In conclusion, the lack of clinical response of a rather high percentage of patients with pituitary adenomas to the currently available drugs could be due not only to an inadequate characterisation of the pituitary tumour receptor profile, but also to the fact that a sort of cell specificity in the response may affect the final outcome. Moreover, in this scenario, we should also consider the new insight of receptor dimerisation. Dimerisation is fairly common in the GPCR superfamily, and overwhelming amounts of data suggest that many GPCRs, including SSRs and DRs, exhibit functional properties that require direct or indirect interactions between clustered receptors. The integration of this property of the SSRs and DRs in the know-how is crucial to elucidate the physiological mechanism of action of certain hormones, while an understanding of the mechanisms involved in these events could offer a rationale in next drug design, also for tumours arising form other cells expressing GPCRs.


   Declaration of interest
Top
 Abstract
 Introduction
 Heterogeneity of somatostatin...
 Functional role of somatostatin...
 The emerging concept of...
 Declaration of interest
Funding
 References
 
The authors declare that there is no conflict of interest that would prejudice the impartiality of this work.


   Funding
Top
 Abstract
 Introduction
 Heterogeneity of somatostatin...
 Functional role of somatostatin...
 The emerging concept of...
 Declaration of interest
 Funding
References
 
This study was partially supported by grants from Italian Ministry of University and Scientific and Technological Research (MIUR 2007RFFFFN_005) and from University of Genova.


   References
Top
 Abstract
 Introduction
 Heterogeneity of somatostatin...
 Functional role of somatostatin...
 The emerging concept of...
 Declaration of interest
 Funding
 References
 
Andersen M, Bjerre P, Schrøder HD, Edal A, Høilund-Carlsen PF, Pedersen PH & Hagen C 2001 In vivo secretory potential and the effect of combination therapy with octreotide and cabergoline in patients with clinically non-functioning pituitary adenomas. Clinical Endocrinology 54 23–30.[CrossRef][Medline]

Asa S, Kovacs K, Horvath E, Singer W & Smyth HS 1992 Hormone secretion in vitro by plurihormonal pituitary adenomas of the acidophilic cell line. Journal of Clinical Endocrinology and Metabolism 75 68–75.[Abstract]

Batista DL, Zhang X, Gejman R, Ansell PJ, Zhou Y, Johnson SA, Swearingen B, Hedley-Whyte ET, Stratakis CA & Klibanski A 2006 The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 91 4482–4488.[Abstract/Free Full Text]

Beck-Peccoz P & Persani L 2002 Medical management of thyrotropin-secreting pituitary adenomas. Pituitary 5 83–88.[CrossRef][Medline]

Ben-Jonathan N & Hnasko R 2001 Dopamine as a prolactin (PRL) inhibitor. Endocrine Reviews 22 724–7638.[Abstract/Free Full Text]

Ben-Shlomo A & Melmed S 2007 Pasireotide: a somatostatin analog for the potential treatment of acromegaly, neuroendocrine tumors and Cushing's disease. Drugs 10 885–895.

Bevan JS 2005 Clinical review: the antitumoral effects of somatostatin analog therapy in acromegaly. Journal of Clinical Endocrinology and Metabolism 90 1856–1863.[Abstract/Free Full Text]

de Bruin C, Feelders RA, Lamberts SWJ & Hofland LJ 2009 Somatostatin and dopamine receptors as targets for medical treatment of Cushing's Syndrome. Reviews in Endocrine and Metabolic Disorders 42 47–56.

de Bruin C, Feelders R, Waaijers M, van Koetsveld P, Sprij-Mooij D, Lamberts S & Hofland L 2008a Differential regulation of human dopamine D2 and somatostatin receptor subtype expression by glucocorticoids in vitro. Journal of Molecular Endocrinology 149 4357–4366.

de Bruin C, Hanson JM, Meij BP, Kooistra HS, Waaijers AM, Uitterlinden P, Lamberts SWJ & Hofland LJ 2008b Expression and functional analysis of dopamine D2 and somatostatin receptor subtypes in canine Cushing's disease. Endocrinology 149 4357–4366.[Abstract/Free Full Text]

Burt MG & Ho KKY 2006 Newer options in the management of acromegaly. Internal Medicine Journal 36 437–444.[CrossRef][Web of Science][Medline]

Casarini AP, Pinto EM, Jallad RS, Giorgi RR, Giannella-Neto D & Bronstein MD 2006 Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3. Journal of Endocrinological Investigation 29 826–830.[Medline]

Colao A, Filippella M, Pivonello R, Di Somma C, Faggiano A & Lombardi G 2007 Combined therapy of somatostatin analogues and dopamine agonists in the treatment of pituitary tumours. European Journal of Endocrinology 156 S57–S63.[Abstract/Free Full Text]

Colao A, Di Somma C, Pivonello R, Faggiano A, Lombardi G & Savastano S 2008 Medical therapy for clinically non-functioning pituitary adenomas. Endocrine-Related Cancer 15 905–915.[Abstract/Free Full Text]

Cozzi R, Attanasio R, Lodrini S & Lasio G 2004 Cabergoline addition to depot somatostatin analogues in resistant acromegalic patients: efficacy and lack of predictive value of prolactin status. Clinical Endocrinology 61 209–215.[CrossRef][Medline]

Cozzi R, Montini M, Attanasio R, Albizzi M, Lasio G, Lodrini S, Doneda P, Cortesi L & Pagani G 2006 Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. Journal of Clinical Endocrinology and Metabolism 91 1397–1403.[Abstract/Free Full Text]

Cremonini N, Graziano E, Chiarini V, Sforza A & Zampa GA 1992 Atypical McCune-Albright syndrome associated with growth hormone-prolactin pituitary adenoma: natural history, long-term follow-up, and SMS 201–995 – bromocriptine combined treatment results. Journal of Clinical Endocrinology and Metabolism 75 1166–1169.[Abstract]

Durán-Prado M, Malagón MM, Gracia-Navarro F & Castaño JP 2008 Dimerization of G protein-coupled receptors: new avenues for somatostatin receptor signalling, control and functioning. Molecular and Cellular Endocrinology 286 63–68.[CrossRef][Web of Science][Medline]

Ferone D, Pivonello R, Lastoria S, Faggiano A, Del Basso de Caro ML, Cappabianca P, Lombardi G & Colao A 2001 In vivo and in vitro effects of octreotide, quinagolide and cabergoline in four hyperprolactinaemic acromegalics: correlation with somatostatin and dopamine D2 receptor scintigraphy. Clinical Endocrinology 54 469–477.[CrossRef][Medline]

Ferone D, Arvigo M, Semino C, Jaquet P, Saveanu A, Taylor JE, Moreau JP, Culler MD, Albertelli M, Minuto F et al. 2005 Somatostatin and dopamine receptor expression in lung carcinoma cells and effects of chimeric somatostatin-dopamine molecules on cell proliferation. American Journal of Physiology. Endocrinology and Metabolism 289 E1044–E1050.[Abstract/Free Full Text]

Ferone D, Pivonello R, Resmini E, Boschetti M, Rebora A, Albertelli M, Albanese V, Colao A, Culler MD & Minuto F 2007a Preclinical and clinical experiences with the role of dopamine receptors in the treatment of pituitary adenomas. European Journal of Endocrinology 156 S37–S43.[Abstract/Free Full Text]

Ferone D, Saveanu A, Culler MD, Arvigo M, Rebora A, Gatto F, Minuto F & Jaquet P 2007b Novel chimeric somatostatin analogs: facts and perspectives. European Journal of Endocrinology 156 S23–S28.[Abstract/Free Full Text]

Ferone D, de Herder WW, Pivonello R, Kros JM, van Koetsveld PM, de Jong T, Minuto F, Colao A, Lamberts SWJ & Hofland LJ 2008 Correlation of in vitro and in vivo somatotropic adenoma responsiveness to somatostatin analogs and dopamine agonists with immunohistochemical evaluation of somatostatin and dopamine receptors and electron microscopy. Journal of Clinical Endocrinology and Metabolism 93 1412–1417.[Abstract/Free Full Text]

Fløgstad AK, Halse J, Grass P, Abisch E, Djøseland O, Kutz K, Bodd E & Jervell J 1994 A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly. Journal of Clinical Endocrinology and Metabolism 79 461–465.[Abstract]

Florio T 2008 Somatostatin/somatostatin receptor signalling: phosphotyrosine phosphatases. Molecular and Cellular Endocrinology 286 40–48.[CrossRef][Web of Science][Medline]

Florio T, Barbieri F, Spaziante R, Zona G, Hofland LJ, van Koetsveld PM, Feelders RA, Stalla GK, Theodoropoulou M, Culler MD et al. 2008 Efficacy of a dopamine-somatostatin chimeric molecule, BIM-23A760, in the control of cell growth from primary cultures of human non-functioning pituitary adenomas: a multi-center study. Endocrine-Related Cancer 15 583–596.[Abstract/Free Full Text]

Freda PU 2002 Somatostatin analogs in acromegaly. Journal of Clinical Endocrinology and Metabolism 87 3013–3018.[Free Full Text]

Fredstorp L, Kutz K & Werner S 1994 Treatment with octreotide and bromocriptine in patients with acromegaly: an open pharmacodynamic interaction study. Clinical Endocrinology 41 103–108.[Medline]

Fusco A, Gunz G, Jaquet P, Dufour H, Germanetti AL, Culler MD, Barlier A & Saveanu A 2007 Somatostatinergic ligands in dopamine-sensitive or -resistant prolactinomas. European Journal of Endocrinology 158 595–603.[Web of Science]

Gillam MP, Molitch ME, Lombardi G & Colao A 2006 Advances in the treatment of prolactinomas. Endocrine Reviews 27 485–534.[Abstract/Free Full Text]

Grant M, Alturaihi H, Jaquet P, Collier B & Kumar U 2008 Cell growth inhibition and functioning of human somatostatin receptor type 2 are modulated by receptor heterodimerization. Molecular Endocrinology 22 2278–2292.[Abstract/Free Full Text]

Greenman Y 2007 Dopaminergic treatment of nonfunctioning pituitary adenomas. Nature Clinical Practice. Endocrinology & Metabolism 3 554–555.[CrossRef][Web of Science][Medline]

Gruszka A, Kunert-Radek J, Radek A, Pisarek H, Taylor J, Dong JZ, Culler MD & Pawlikowski M 2006 The effect of selective sst1, sst2, sst5 somatostatin receptors agonists, a somatostatin/dopamine (SST/DA) chimera and bromocriptine on the ‘clinically non-functioning’ pituitary adenomas in vitro. Life Science 78 689–693.[CrossRef][Web of Science][Medline]

Guillemin R 2005 Hypothalamic hormones a.k.a. hypothalamic releasing factors. Journal of Endocrinology 184 11–28.[Abstract/Free Full Text]

Hofland LJ & Lamberts SW 2001 Somatostatin receptor subtype expression in human tumors. Annals of Oncology 12 S31–S36.[Abstract]

Hofland LJ & Lamberts SWJ 2003 The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Reviews 24 28–47.[Abstract/Free Full Text]

Kidd M, Modlin IM, Black JW, Boyce M & Culler M 2007 A comparison of the effects of gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation. Regulatory Peptides 143 109–117.[CrossRef][Web of Science][Medline]

Kidd M, Drozdov I, Joseph R, Pfragner R, Culler M & Modlin I 2008 Differential cytotoxicity of novel somatostatin and dopamine chimeric compounds on bronchopulmonary and small intestinal neuroendocrine tumor cell lines. Cancer 113 690–700.[CrossRef][Web of Science][Medline]

Lahlou H, Guillermet J, Hortala M, Vernejoul F, Pyronnet S, Bousquet C & Susini C 2004 Molecular signaling of somatostatin receptors. Annals of the New York Academy of Sciences 1014 121–131.[CrossRef][Web of Science][Medline]

Lamberts SW, Zweens M, Verschoor L & del Pozo E 1986 A comparison among the growth hormone-lowering effects in acromegaly of the somatostatin analog SMS 201–995, bromocriptine, and the combination of both drugs. Journal of Clinical Endocrinology and Metabolism 63 16–19.[Abstract/Free Full Text]

Lesche S, Lehmann D, Nagel F, Schmid HA & Schulz S 2009 Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. Journal of Clinical Endocrinology and Metabolism 94 654–661.[Abstract/Free Full Text]

Li JK, Chow CC, Yeung VT, Mak TW, Ko GT, Swaminathan R, Chan JC & Cockram CS 2000 Treatment of Chinese acromegaly with a combination of bromocriptine and octreotide. Australian and New Zealand Journal of Medicine 30 457–461.[Web of Science][Medline]

Marzullo P, Ferone D, Di Somma C, Pivonello R, Filippella M, Lombardi G & Colao A 1999 Efficacy of combined treatment with lanreotide and cabergoline in selected therapy-resistant acromegalic patients. Pituitary 1 115–120.[CrossRef][Medline]

Miller GM, Alexander JM, Bikkal HA, Katznelson L, Zervas NT & Klibanski A 1995 Somatostatin receptor subtype gene expression in pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 80 1386–1392.[Abstract]

Minniti G, Jaffrain-Rea ML, Baldelli R, Ferretti E, Caracciolo B, Bultrini A, Gulino A & Tamburrano G 1997 Acute effects of octreotide, cabergoline and a combination of both drugs on GH secretion in acromegalic patients. Clinica Terapeutica 148 601–607.[Medline]

Missale C, Nash SR, Robinson SW, Jaber M & Caron MG 1998 Dopamine receptors: from structure to function. Physiological Reviews 78 189–225.[Abstract/Free Full Text]

Moller LN, Stidsen CE, Hartmann B & Holst JJ 2003 Somatostatin receptors. Biochimica et Biophysica Acta 1616 1–84.[Medline]

Ness-Abramof R, Ishay A, Harel G, Sylvetzky N, Baron E, Greenman Y & Shimon I 2007 TSH-secreting pituitary adenomas: follow-up of 11 cases and review of the literature. Pituitary 10 307–310.[CrossRef][Web of Science][Medline]

Ono K, Suzuki T, Miki Y, Taniyama Y, Nakamura Y, Noda Y, Watanabe M & Sasano H 2007 Somatostatin receptor subtypes in human non-functioning neuroendocrine tumors and effects of somatostatin analogue SOM230 on cell proliferation in cell line NCI-H727. Anticancer Research 27 2231–2239.[Abstract/Free Full Text]

Panetta R & Patel YC 1995 Expression of mRNA for all five human somatostatin receptors (hSSTR1-5) in pituitary tumors. Life Sciences 56 333–342.[CrossRef][Web of Science][Medline]

Pasquali D, Rossi V, Conzo G, Pannone G, Bufo P, De Bellis A, Renzullo A, Bellastella G, Colao A, Vallone G et al. 2008 Effects of somatostatin analog SOM230 on cell proliferation, apoptosis, and catecholamine levels in cultured pheochromocytoma cells. Journal of Molecular Endocrinology 40 263–271.[Abstract/Free Full Text]

Pivonello R, Ferone D, de Herder WW, Kros JM, De Caro ML, Arvigo M, Annunziato L, Lombardi G, Colao A, Hofland LJ et al. 2004a Dopamine receptor expression and function in corticotroph pituitary tumors. Journal of Clinical Endocrinology and Metabolism 89 2452–2462.[Abstract/Free Full Text]

Pivonello R, Matrone C, Filippella M, Cavallo LM, Di Somma C, Cappabianca P, Colao A, Annunziato L & Lombardi G 2004b Dopamine receptor expression and function in clinically nonfunctioning pituitary tumors: comparison with the effectiveness of cabergoline treatment. Journal of Clinical Endocrinology and Metabolism 89 1674–1683.[Abstract/Free Full Text]

Pivonello R, Ferone D, Lamberts SW & Colao A 2005 Cabergoline plus lanreotide for ectopic Cushing's syndrome. New England Journal of Medicine 352 2457–2458.[Free Full Text]

Popovic V, Nesovic M, Micic D, Kendereski A, Djordjevic P, Manojlovic D & Micic J 1990 A comparison among the effectiveness of growth hormone suppression in active acromegaly of bromocriptine and long acting somatostatin analogue (SMS 201–995). Experimental and Clinical Endocrinology 95 251–257.[Web of Science][Medline]

Renner U, Arzberger T, Pagotto U, Leimgruber S, Uhl E, Muller A, Lange M, Weindl A & Stalla GK 1998 Heterogeneous dopamine D2 receptor subtype messenger ribonucleic acid expression in clinically nonfunctioning pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 83 1368–1375.[Abstract/Free Full Text]

Resmini E, Dadati P, Ravetti JL, Zona G, Spaziante R, Saveanu A, Jaquet P, Culler MD, Bianchi F, Rebora A et al. 2007 Rapid pituitary tumor shrinkage with dissociation between antiproliferative and antisecretory effects of a long-acting octreotide in an acromegalic patient. Journal of Clinical Endocrinology and Metabolism 92 1592–1599.[Abstract/Free Full Text]

Rocheville M, Lange DC, Kumar U, Patel SC, Patel RC & Patel YC 2000 Receptors for dopamine and somatostatin: formation of heterooligomers with enhanced functional activity. Science 288 154–157.[Abstract/Free Full Text]

Sadoul JL, Thyss A & Freychet P 1992 Invasive mixed growth hormone/prolactin secreting pituitary tumour: complete shrinking by octreotide and bromocriptine, and lack of tumour growth relapse 20 months after octreotide withdrawal. Acta Endocrinologica 126 179–183.[Abstract/Free Full Text]

Saveanu A & Jaquet P 2008 Somatostatin-dopamine ligands in the treatment of pituitary adenomas. Reviews in Endocrine and Metabolic Disorders(Epub ahead of print)

Saveanu A, Jaquet P, Brue T & Barlier A 2008 Relevance of coexpression of somatostatin and dopamine D2 receptors in pituitary adenomas. Molecular and Cellular Endocrinology 286 206–213.[CrossRef][Web of Science][Medline]

Saveanu A, Gunz G, Dufour H, Caron P, Fina F, Ouafik L, Culler MD, Moreau JP, Enjalbert A & Jaquet P 2001 BIM-23244, a somatostatin receptor subtype 2- and 5-selective analog with enhanced efficacy in suppressing growth hormone (GH) from octreotide-resistant human GH-secreting adenomas. Journal of Clinical Endocrinology and Metabolism 86 140–145.[Abstract/Free Full Text]

Saveanu A, Gunz G, Guillen S, Dufour H, Culler MD & Jaquet P 2006 Somatostatin and dopamine-somatostatin multiple ligands directed towards somatostatin and dopamine receptors in pituitary adenomas. Neuroendocrinology 83 258–263.[CrossRef][Web of Science][Medline]

Schonbrunn A 2008 Selective agonism in somatostatin receptor signaling and regulation. Molecular and Cellular Endocrinology 286 35–39.[CrossRef][Web of Science][Medline]

Selvarajah D, Webster J, Ross R & Newell-Price J 2005 Effectiveness of adding dopamine agonist therapy to long-acting somatostatin analogues in the management of acromegaly. European Journal of Endocrinology 152 569–574.[Abstract/Free Full Text]

Stefaneanu L, Kovacs K, Horvath E, Buchfelder M, Fahlbusch R & Lancranjan L 2001 Dopamine D2 receptor gene expression in human adenohypophysial adenomas. Endocrine 14 329–336.[CrossRef][Web of Science][Medline]

Taboada GF, Luque RM, Bastos W, Guimaraes RF, Marcondes JB, Chimelli LM, Fontes R, Mata PJ, Filho PN, Carvalho DP et al. 2007 Quantitative analysis of somatostatin receptor subtype (SSTR1-5) gene expression levels in somatotropinomas and non-functioning pituitary adenomas. European Journal of Endocrinology 156 65–74.[Abstract/Free Full Text]

Theodoropoulou M, Zhang J, Laupheimer S, Paez-Pereda M, Erneux C, Florio T, Pagotto U & Stalla GK 2006 Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Research 66 1576–1582.[Abstract/Free Full Text]

Trouillas J, Chevallier P, Remy C, Rajas F, Cohen R, Calle A, Hooghe-Peters EL & Rousset B 1999 Differential action of the dopamine agonist bromocriptine on growth of SMtTW tumor exhibiting a prolactin and/or somatotroph cell phenotype: relation to dopamine D2 receptor expression. Endocrinology 140 13–21.[Abstract/Free Full Text]

Tulipano G & Schulz S 2007 Novel insights in somatostatin receptor physiology. European Journal of Endocrinology 156 S3–S11.[Abstract/Free Full Text]

Wagenaar AH, Harris AG, van der Lely AJ & Lamberts SW 1991 Dynamics of the acute effects of octreotide, bromocriptine and both drugs in combination on growth hormone secretion in acromegaly. Acta Endocrinologica 125 637–642.[Abstract/Free Full Text]

Yoshihara A, Isozaki O, Hizuka N, Nozoe Y, Harada C, Ono M, Kawamata T, Kubo O, Hori T & Takano K 2007 Expression of type 5 somatostatin receptor in TSH-secreting pituitary adenomas: a possible marker for predicting long-term response to octreotide therapy. Endocrine Journal 54 133–138.[CrossRef][Web of Science][Medline]

Zatelli MC, Piccin D, Tagliati F, Ambrosio MR, Margutti A, Padovani R, Scanarini M, Culler MD & degli Uberti EC 2003 Somatostatin receptor subtype 1 selective activation in human growth hormone (GH)- and prolactin (PRL)-secreting pituitary adenomas: effects on cell viability, GH, and PRL secretion. Journal of Clinical Endocrinology and Metabolism 88 2797–2802.[Abstract/Free Full Text]

Zatelli MC, Piccin D, Bottoni A, Ambrosio MR, Margutti A, Padovani R, Scanarini M, Taylor JE, Culler MD, Cavazzini L et al. 2004 Evidence for differential effects of selective somatostatin receptor subtype agonists on alpha-subunit and chromogranin a secretion and on cell viability in human nonfunctioning pituitary adenomas in vitro. Journal of Clinical Endocrinology and Metabolism 89 5181–5188.[Abstract/Free Full Text]

Zatelli MC, Piccin D, Tagliati F, Bottoni A, Ambrosio MR, Margutti A, Scanarini M, Bondanelli M, Culler MD & degli Uberti EC 2005 Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro. Journal of Molecular Endocrinology 35 333–341.[Abstract/Free Full Text]

Received in final form 8 January 2009
Accepted 13 January 2009
Made available online as an Accepted Preprint 13 January 2009




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