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

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

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 thyroid hormone triiodothyronine controls macrophage maturation and functions: protective role during inflammation.

The endocrine system participates in regulating macrophage maturation, although little is known about the modulating role of the thyroid hormones. In vitro results demonstrate a negative role of one such hormone, triiodothyronine (T 3 ), in triggering the differentiation of bone marrow–derived monocytes into unpolarized macrophages. T 3 -induced macrophages displayed a classically activated (M1) signature. A T 3 -induced M1-priming effect was also observed on polarized macrophages because T 3 reverses alternatively activated (M2) activation, whereas it enhances that of M1 cells. In vivo , circulating T 3 increased the content of the resident macrophages in the peritoneal cavity, whereas it reduced the content of the recruited monocyte-derived cells. Of interest, T 3 significantly protected mice against endotoxemia induced by lipopolysaccharide i.p. injection; in these damaged animals, decreased T 3 levels increased the recruited (potentially damaging) cells, whereas restoring T 3 levels decreased recruited and increased resident (potentially beneficial) cells. These data suggest that the anti-inflammatory effect of T 3 is coupled to the modulation of peritoneal macrophage content, in a context not fully explained by the M1/M2 framework. Thyroid hormone receptor expression analysis and the use of different thyroid hormone receptor antagonists suggest thyroid hormone receptor β1 as the major player mediating T 3 effects on macrophages. The novel homeostatic link between thyroid hormones and the pathophysiological role of macrophages opens new perspectives on the interactions between the endocrine and immune systems

Interleukin 18 in the CNS

Interleukin (IL)-18 is a cytokine isolated as an important modulator of immune responses and subsequently shown to be pleiotropic. IL-18 and its receptors are expressed in the central nervous system (CNS) where they participate in neuroinflammatory/neurodegenerative processes but also influence homeostasis and behavior. Work on IL-18 null mice, the localization of the IL-18 receptor complex in neurons and the neuronal expression of decoy isoforms of the receptor subunits are beginning to reveal the complexity and the significance of the IL-18 system in the CNS. This review summarizes current knowledge on the central role of IL-18 in health and disease

The secondary metabolite euplotin c induces apoptosis-like death in the marine ciliated protist euplotes vannus

The sesquiterpenoid euplotin C is a secondary metabolite produced by the ciliated protist Euplotes crassus and provides a mechanism for damping populations of potential competitors. Indeed, E. crassus is virtually resistant to its own product while different non-producer species representing an unbiased sample of the marine, interstitial, ciliate diversity are sensitive. For instance, euplotin C exerts a marked disruption of different homeostatic mechanisms in Euplotes vannus. We demonstrate by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay that euplotin C quickly decreases viability and mitochondrial function of E. vannus with a very high efficacy and at micromolar potency. In addition, euplotin C induces apoptosis in E. vannus as 4,6-diamino-2-phenylindole and Terminal Transferase dUTP Nick End Labeling staining show the rapid condensation and fragmentation of nuclear material in cells treated with euplotin C. These effects occur without detectable permeabilisation or rupture of cell membranes and with no major changes in the overall morphology, although some traits, such as vacuolisation and disorganised microtubules, can be observed by transmission electron microscopy. In particular, E. vannus show profound changes of the mitochondrial ultrastructure. Finally, we also show that caspase activity in E. vannus is increased by euplotin C. These data elucidate the pro-apoptotic role of euplotin C and suggest a mechanism for its impact on natural selection.L'articolo è disponibile sul sito dell'editore http://onlinelibrary.wiley.com