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.
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- Abstract: Pituitary x
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- Abstract: somatostatin x
Diego Ferone, Federico Gatto, Marica Arvigo, Eugenia Resmini, Mara Boschetti, Claudia Teti, Daniela Esposito and Francesco Minuto
T Florio and G Schettini
Somatostatin is a peptide widely distributed in both the central nervous system (CNS) and peripheral tissues. It is found as two bioactive peptides of 14 and 28 amino acids, the latter being an N-terminal-extended form (Reichlin 1983a).
The name somatostatin comes from its initial discovery as an inhibitor of growth hormone (GH) release from anterior pituitary cells (Brazeau et al. 1973). Since then, numerous other physiological activities of somatostatin have been discovered associated with differing peptide and receptor localization (Reichlin 1983a,b). Besides GH, somatostatin is also able to inhibit secretion of prolactin (PRL) and thyroid-stimulating hormone (TSH) (Reichlin 1983a). In the CNS, the highest somatostatin concentrations have been detected in the hypothalamus in the tuberoinfundibular neurons where, acting as a neurohormone, the peptide regulates the hypothalamic-hypophyseal axis (Schettini 1991). Somatostatin-containing neurons are also present in many other areas of the brain, such as the cerebral cortex,
C de Bruin, R A Feelders, A M Waaijers, P M van Koetsveld, D M Sprij-Mooij, S W J Lamberts and L J Hofland
Dopamine agonists (DA) and somatostatin (SS) analogues have been proposed in the treatment of ACTH-producing neuro-endocrine tumours that cause Cushing's syndrome. Inversely, glucocorticoids (GCs) can differentially influence DA receptor D2 or SS receptor subtype (sst) expression in rodent models. If this also occurs in human neuro-endocrine cells, then cortisol-lowering therapy could directly affect the expression of these target receptors. In this study, we investigated the effects of the GC dexamethasone (DEX) on D2 and sst expression in three human neuro-endocrine cell lines: BON (carcinoid) and TT (medullary thyroid carcinoma) versus DMS (small cell lung cancer), which is severely GC resistant. In BON and TT, sst2 mRNA was strongly down-regulated in a dose-dependent manner (IC50 0.84 nM and 0.16 nM), whereas sst5 and especially D2 were much more resistant to DEX treatment. Sst2 down-regulation was abrogated by a GC receptor antagonist and reversible in time upon GC withdrawal. At the protein level, DEX also induced a decrease in the total number of SS (−52%) and sst2-specific (−42%) binding sites. Pretreatment with DEX abrogated calcitonin inhibition by sst2-preferring analogue octreotide in TT. In DMS, DEX did not cause significant changes in the expression of these receptor subtypes. In conclusion, we show that GCs selectively down-regulate sst2, but not D2 and only to a minor degree sst5 in human neuro-endocrine BON and TT cells. This mechanism may also be responsible for the low expression of sst2 in corticotroph adenomas and underwrite the current interest in sst5 and D2 as possible therapeutic targets for a medical treatment of Cushing's disease.
R M Luque, J R Peinado, F Gracia-Navarro, F Broglio, E Ghigo, R D Kineman, M M Malagón and J P Castaño
Cortistatin is a recently discovered neuropeptide that is structurally related to somatostatin, the classic inhibitor of growth hormone (GH) release. Cortistatin binds with high affinity to all five somatostatin receptors (sst1–5), and, like somatostatin, cortistatin inhibits in vivo GH release in man and rats. In this report, we compared the in vitro actions of cortistatin and somatostatin using primary pig pituitary cell cultures. In this species, we have previously reported that somatostatin not only inhibits GH-releasing hormone (GHRH)-stimulated GH release at high doses, but also stimulates basal GH release at low (pM) doses, a dual response that is markedly dependent on the subpopulation of pituitary somatotropes examined. Results reported herein demonstrate that cortistatin closely mimics the dose-dependent inhibitory and stimulatory effects of somatostatin on GH secretion. As cortistatin, unlike somatostatin, binds to the human receptor for ghrelin/GH secretagogs (GHS-R), we also investigated whether cortistatin stimulates GH release through this receptor by using a synthetic, short form of cortistatin, cortistatin-8 (CST8), which lacks the sst-binding capacity of full-length cortistatin but retains its GHS-R-binding capacity. Interestingly, CST8 stimulated GH release only at low doses (10−15 M), and did not reduce GH secretion stimulated by GHRH, ghrelin, or low-dose, full-length cortistatin, yet it counteracted that induced by a nonpeptidyl GHS, L-163 255. Taken together, our results indicate that the dual, inhibitory and stimulatory effects of cortistatin on GH release closely parallel those of somatostatin and are probably mediated by the same receptor(s) and signaling pathway(s) for both peptides. Furthermore, they suggest that the pathway(s) activated by cortistatin (and somatostatin) to stimulate GH release are not initiated by GHS-R activation.
Clemens Wagner, S Roy Caplan and Gloria S Tannenbaum
Growth hormone (GH) is secreted in a pulsatile fashion from the pituitary gland into the circulation. Release is governed by two hypothalamic neuropeptides, growth hormone-releasing hormone (GHRH) and somatostatin (SRIF), resulting in secretion episodes with a periodicity of 3.3 h in the male rat. Ghrelin is an additional recently identified potent GH-secretagogue. However, its in vivo interactions with the GH neuroendocrine axis remain to be elucidated. Moreover, two different sites of ghrelin synthesis are involved, the stomach and the hypothalamus. We used our previously developed core model of GH oscillations and added the sites of ghrelin action at the pituitary and in the hypothalamus. With this extended model, we simulated the effects of central and peripheral ghrelin injections, monitored the GH profile and compared it with existing experimental results. Systemically administered ghrelin elicits a GH pulse independent of SRIF, but only in the presence of GHRH. The peripheral ghrelin signal is mediated to the brain via the vagus nerve, where it augments the release of GHRH and stimulates the secretion of neuropeptide-Y (NPY). By contrast, centrally administered ghrelin initiates a GH pulse by increasing the GHRH level and by antagonizing the SRIF block at the pituitary. In addition, NPY neurons are activated, which trigger a delayed SRIF surge. The major novel features of the present model are a) the role played by NPY, and b) the dissimilar functions of ghrelin in the hypothalamus and at the pituitary. Furthermore, the predictions of the model were experimentally examined and confirmed.
Daniel Cuevas-Ramos and Maria Fleseriu
Somatostatin (SST), an inhibitory polypeptide with two biologically active forms SST14 and SST28, inhibits GH, prolactin (PRL), TSH, and ACTH secretion in the anterior pituitary gland. SST also has an antiproliferative effect inducing cell cycle arrest and apoptosis. Such actions are mediated through five G-protein-coupled somatostatin receptors (SSTR): SSTR1–SSTR5. In GH-secreting adenomas, SSTR2 expression predominates, and somatostatin receptor ligands (SRLs; octreotide and lanreotide) directed to SSTR2 are presently the mainstays of medical therapy. However, about half of patients show incomplete biochemical remission, but the definition of resistance per se remains controversial. We summarize here the determinants of SRL resistance in acromegaly patients, including clinical, imaging features as well as molecular (mutations, SSTR variants, and polymorphisms), and histopathological (granulation pattern, and proteins and receptor expression) predictors. The role of SSTR5 may explain the partial responsiveness to SRLs in patients with adequate SSTR2 density in the cell membrane. In patients with ACTH-secreting pituitary adenomas, i.e. Cushing's disease (CD), SSTR5 is the most abundant receptor expressed and tumors show low SSTR2 density due to hypercortisolism-induced SSTR2 down-regulation. Clinical studies with pasireotide, a multireceptor-targeted SRL with increased SSTR5 activity, lead to approval of pasireotide for treatment of patients with CD. Other SRL delivery modes (oral octreotide), multireceptor-targeted SRL (somatoprim) or chimeric compounds targeting dopamine D2 receptors and SSTR2 (dopastatin), are briefly discussed.
R. S. Boyd, K. P. Ray and M. Wallis
Forskolin and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate stimulate prolactin and GH release from ovine anterior pituitary cells cultured in vitro. Dopamine and somatostatin inhibit release of prolactin and GH respectively, after stimulation by these agents, but without effects on intracellular cyclic AMP concentrations. In each case the inhibitory effects were reversed by pre-treatment of cells with pertussis toxin, in a dose-related fashion (1–100 ng/ml), again without affecting cyclic AMP levels. The results suggest that the inhibitory effects of dopamine and somatostatin in this system are mediated by one or more pertussis toxin-sensitive G proteins, and that these act by a mechanism which does not involve inhibition of adenylate cyclase.
BJ Slagter and MA Sheridan
Somatostatins (SSs) play important roles in the growth, development and metabolism of vertebrates. In this study, cDNAs for two unique somatostatin receptor variants were cloned and sequenced from rainbow trout. The two cDNAs, one consisting of 1755 bp and the other of 1743 bp, share 63.6% identity in nucleotide sequence and 94.1% identity in deduced amino acid sequence and presumably arose through gene duplication. Each cDNA encodes for a putative 371-amino acid somatostatin receptor (one designated sst1A and the other sst1B) containing seven transmembrane domains. Rainbow trout sst1A and sst1B have 64.4 and 65.5% similarity respectively with human sst1 and only 43-60% similarity with other subtypes. Trout sst1 mRNAs are differentially expressed, both in terms of distribution among tissues as well as in terms of abundance within selected tissues. Both sst1A and sst1B mRNAs were present in brain, stomach, liver, pancreas, upper and lower intestine, pyloric cecum, kidney and muscle, whereas only sst1B mRNA was present in the esophagus. sst1A mRNA was more abundant than sst1B in the optic tectum, whereas sst1B mRNA was more abundant than sst1A in liver. sst1A and sst1B mRNAs were equally abundant in pancreas. These findings contribute to the understanding of the evolution of the SS signaling system and provide insight into the mechanisms that regulate the expression of SS receptors.
A. Levy and S. L. Lightman
We have examined the effects of human GH-releasing factor (1–44) (GRF), cortisol and somatostatin-(1–14) on GH gene expression in solid tissue and dispersed cells from human pituitary adenomas using quantitative in-situ hybridization histochemistry. Sections cut from tissue obtained at hypophysectomy from three acromegalic patients were hybridized to probes directed against mature α-subunit, GH, prolactin, pro-opiomelanocortin, TSHβ-subunit and LHβ-subunit mRNA. Only one biopsy contained GH mRNA in isolation. A second was found to co-exhibit GH, prolactin and α-subunit mRNA, and a third was found to contain prolactin, TSHβ-subunit, α-subunit and LHβ-subunit mRNA, with GH mRNA below the limit of specific detection, indicating that the sample was composed of normal rather than adenomatous pituitary tissue. GH mRNA in individual dispersed cells derived from the latter declined to barely detectable levels over 287 h, both in cultures containing GRF (10 ng/ml) or GRF (10 ng/ml) plus somatostatin (10 ng/ml) and in controls, but increased fourfold in cultures containing GRF (10 ng/ml) plus cortisol (0·5 μmol/l). GH mRNA remained unchanged in both adenoma samples over 138 and 450 h, irrespective of the addition of GRF or GRF plus hydrocortisone. In these samples, somatostatin plus GRF had no consistent effect. These studies confirm that quantitative in-situ hybridization histochemistry can be used to investigate hormone gene regulation in small samples of human tissue and should enable us to define more clearly the level at which abnormal gene regulation occurs.
J S Davies, J L Holter, D Knight, S M Beaucourt, D Murphy, D A Carter and T Wells
Targeted overexpression of biologically active peptides represents a powerful approach to the functional dissection of neuroendocrine systems. However, the requirement to generate separate, biologically active and reporter molecules necessitates the use of internal ribosome entry site (IRES) technology, which often results in preferential translation of the second cistron. We report here a novel approach in which the proteolytic processing machinery of the regulated secretory pathway (RSP) has been exploited to generate multiple mature proteins from a monocistronic construct that encodes a single precursor. This was achieved by duplication of the pre-pro cleavage sites in pre-prosomatostatin cDNA. The duplicated site included 10 flanking amino acids on either side of the Gly-Ala cleavage position. This enabled the incorporation of a foreign protein-coding sequence (in this case, enhanced green fluorescent protein (eGFP)) between these sites. The pre-eGFP-prosomatostatin (PEPS) construct generated co-localized expression of fully processed eGFP and somatostatin to the RSP of transiently transfected AtT20 cells. This approach represents an advance upon bicistronic and other extant approaches to the targeting of multiple, biologically active proteins to neuroendocrine systems, and, importantly, permits the co-expression of fluorescent markers with biologically active neuropeptides. In this study, our demonstration of the fusion of the first 10 amino acids of the prosomatostatin sequence to the N-terminus of eGFP shows that this putative sorting sequence is sufficient to direct expression to the RSP.