Native somatostatin sst2 and sst5 receptors functionally coupled to Gi/o-protein, but not to the serum response element in AtT-20 mouse tumour corticotrophs

Of the five cloned somatostatin (SRIF: somatotropin release inhibitory factor) receptors (sst1-5), only sst2 and sst5 receptors appear to be endogenously expressed and functionally active in AtT-20 mouse anterior pituitary tumour cells. In this study, the presence and the functional coupling of SRIF receptors to G-protein in AtT-20 cells was evaluated by receptor autoradiography and guanosine-5′-O-(3-[35S]thio)-triphosphate ([35S]GTPγS) binding, respectively. In addition, transcriptional effects via the serum response element (SRE) were assessed in AtT-20-SRE-luci cells, engineered to express constitutively SRE upstream of the luciferase reporter gene. [125I]LTT-SRIF-28, [125I]CGP 23996 and [125I]Tyr3-octreotide binding illustrates the high level of sst2/5 receptor in AtT-20 cell membranes. SRIF-14 and SRIF-28 produced a concentration-dependent increase in [35S]GTPγS binding (pEC50 = 6.72 and 7.45; Emax = 79 and 74.9, respectively) which was completely abolished by pertussis toxin, sst2/5 receptor-selective ligands caused a concentration-dependent increase in [35S]GTPγS binding (pEC50 = 7.74-5.84; Emax = 76.6-20.2) while SSt1/3/4 receptor-selective ligands were devoid of activity. The binding profiles of [125I]LTT-SRIF-28 and the inhibition of cAMP accumulation correlated highly significantly with their corresponding [35S]GTPγS binding profiles (r=0.862 and 0.874, respectively). The effects of the sst2 receptor-preferring agonists Tyr3-octreotide and BIM 23027 on [35S]GTPγS binding, but not those of SRIF-14 and the sst5/1 receptor selective-agonist L-817,818, were competitively antagonised by the sst2 receptor antagonist D-Tyr8-CYN 154806 (pKB = 7.36 and 7.72, respectively; slope factors not significantly different from unity). In AtT-20-SRE-luci cells, which carry a SRE-luciferase construct functioning in a very efficient manner, SRIF and its analogues did not affect luciferase activity. Taken together, these results demonstrate that in AtT-20 cells the expression of sst2 and sst5 receptors fit with their functional coupling to Gi/o-proteins. The pharmacological implications of the existence of different ligand/receptor complexes are discussed. However, the intracellular pathways coupled to the activation of sst2 and sst5 receptors appear not to modulate the SRE-mediated transcriptional activity, suggesting that SRIF effects on gene expression coupled to mechanisms that have promoters other than SRE.L'articolo è disponibile sul sito dell'editore http://www.springerlink.com

An update on somatostatin receptor signaling in native systems and new insights on their pathophysiology

The peptide somatostatin (SRIF) has important physiological effects (mostly inhibitory) which have formed the basis for the clinical use of SRIF compounds. SRIF binding to its five G-protein coupled receptors leads to the modulation of multiple transduction pathways. However, our current understanding of signalling exerted by receptors endogenously expressed in different cells/tissues reflects a rather complicated picture. On the other hand, the complexity of SRIF receptor signalling in pathologies, including pituitary and nervous system diseases, may be studied not only as alternative intervention points for the modulation of SRIF function but also to exploit new chemical space for drug-like molecules.L'articolo è disponibile sul sito dell'editore http://www.sciencedirect.com

Multiple Signalling Transduction Mechanisms Differentially Coupled to Somatostatin Receptor Subtypes: a Current View.

Somatostatin (SRIF) is a cyclic peptide widely distributed throughout the body with important physiological effects (mostly inhibitory) on several organ systems. SRIF may act as a neurohormone, neurotransmitter, neuromodulator or as a local factor, and exhibits potent antiproliferative activity. SRIF effects have formed the basis for the clinical use of SRIF analogues in the treatment of endocrine tumours, acromegaly and gastrointestinal disorders. Several data suggest that SRIF may also be a therapeutic target in a number of different diseases. The binding of SRIF to its five G-protein coupled receptors leads to modulation of multiple transduction pathways, including adenylyl cyclase, guanylyl cyclase, phospholipase C, K+ and Ca2+ channels, phospholipase A2, nitric oxide, Na+/H+ exchanger, protein phosphatases and MAP kinases. The diversity of the transduction pathways reflects the pleiotropic actions of SRIF. However, our current understanding depicts a rather complicated picture and conflicting results have also been reported. Data are mostly based on in vitro experiments, and parallels with the real in vivo conditions are not so obvious. Due to the clinical relevance of the SRIF system, the elucidation of the intracellular role of endogenous SRIF receptors may offer new therapeutic perspectives. These will enable development of specific pharmacological signalling modulators which can be incorporated into the therapeutic arsenal. The present review represents a detailed and exhaustive summary which covers the latest advances in the transduction pathways of SRIF receptors.L'articolo è disponibile sul sito dell'editore http://www.benthamscience.com/index.ht

Expression, pharmacology and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

Somatostatin (SRIF)-14 is recognized as an important mediator between the nervous and the immune system, although the functional role of its receptors (sst1-sst5) is poorly understood in humans. In our study, we demonstrate that human macrophages differentiated from peripheral blood mononuclear cell-derived monocytes express both sst1 and sst2 mRNAs. Both sst1 and sst2 are mostly localized at the cell surface and display active binding sites. In particular, sst1/sst2 activation results in a weak internalization of sst1 while the sst2 internalization appears more efficient. At the functional level, the activation of SRIF receptors by the multiligand analogues SOM230 and KE108, but not by SRIF-14 or cortistatin-14, reduces macrophage viability. Their effects are mimicked by the selective activation of sst1 and sst2 using CH-275 and SMS 201-995/L-779,976, respectively. Further, both sst1- and sst2-mediated effects are reversed by the sst1 antagonist SRA-880 or the sst2 antagonist CYN, respectively. CH-275, SMS 201-995 and L-779,976, but not SRIF-14, decrease both mRNA expression and secretion of the monocyte chemotactic protein-1. In addition, SRIF-14, CH-275, SMS 201-995 and L-779,976 decrease interleukine-8 secretion while they do not affect interleukine-8 mRNA expression. In contrast, SRIF-14 and sst1/sst2 agonists do not affect the secretion of matrix metalloproteinase-9. Collectively, our results suggest that the SRIF system, through sst1 and sst2, exerts mainly an immunosuppressive effect in human macrophages and may, therefore, represent a therapeutic window that can be exploited for the development of new strategies in pharmacological therapy of inflammation.L'articolo è disponibile sul sito dell'editore http://leukocytebiology.org/default.asp

Physiology and pathology of somatostatin in the mammalian retina: a current view

In the retina, peptidergic signalling participates in multiple circuits of visual information processing. The neuropeptide somatostatin (SRIF) is localised to amacrine cells and, in some instances, in a subset of ganglion cells. The variegated expression patterns of SRIF receptors (sst1-sst5) and the variety of signalling mechanisms activated by retinal SRIF suggest that this peptide may exert multiple actions on retinal neurons and on retinal physiology, although our current understanding reflects a rather complicated picture. SRIF, mostly through sst2, may act as a positive factor in the retina by regulating retinal homeostasis and protecting neurons against damage. In this respect, SRIF analogues seem to constitute a promising therapeutic arsenal to cure different retinal diseases, as for instance ischemic and diabetic retinopathies. However, further investigations are needed not only to fully understand the functional role of the SRIF system in the retina but also to exploit new chemical space for drug-like molecules.L'articolo è disponibile sul sito dell'editore http://www.sciencedirect.com

The yellow European eel (Anguilla anguilla L.) may adopt a sedentary lifestyle in inland freshwaters

We analysed the movements of the growing yellow phase using a long-term mark–recapture programme on European eels in a small catchment (the Frémur, France). The results showed that of the yellow eels (>200 mm) recaptured, more than 90% were recaptured at the original marking site over a long period before the silvering metamorphosis and downstream migration. We conclude that yellow European eels >200 mm may adopt a sedentary lifestyle in freshwater area, especially in small catchment