UNIPROT:P61278 - FACTA Search

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Query: UNIPROT:P61278 (somatostatin)
22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The effects of somatostatin and somatostatin analogues on a Ca2+ current from acutely isolated and short-term (24-48 h) cultured adult rat superior cervical ganglion (SCG) neurones were studied using the whole-cell variant of the patch-clamp technique. 2. [D-Trp8]Somatostatin (SOM) produced a rapid, reversible and concentration-dependent reduction of the Ca2+ current. Ca2+ current amplitude was reduced over the voltage range -15 to +40 mV with the greatest reduction occurring where the amplitude was maximal (ca +10 mV). In the presence of SOM, the Ca2+ current rising phase was slower and biphasic at potentials between 0 and +40 mV. 3. Application of 0.1 microM-SOM for greater than 10 s resulted in a desensitization of the response. During a 4 min application of 0.1 microM-SOM, Ca2+ current amplitude returned to about 90% of control. A second application of 0.1 microM-SOM produced less block than the initial application. 4. Concentration-response curves for SOM, somatostatin-14 (SOM-14) and somatostatin-28 (SOM-28) were fitted to a single-site binding isotherm. The concentrations producing half-maximal block and the maximal attainable blocks of the Ca2+ current for SOM, SOM-14 and SOM-28 were 3.3, 5.4 and 35 nM, respectively and 55, 51 and 54%, respectively. SOM-14 and SOM-28 slowed the Ca2+ current rising phase in a manner similar to that of SOM. Somatostatin-28 had no effect on the Ca2+ current at 1 microM. 5. The magnitude of the Ca2+ current block produced by 0.1 microM-SOM was not significantly altered in the presence of 1 microM-idazoxan, atropine, naloxone or the somatostatin antagonist aminoheptanoyl-Phe-D-Trp-Lys-O-benzyl-Thr. 6. Internal dialysis with solutions containing 500 microM-guanylyl-imidodiphosphate (Gpp(NH)p) or guanosine-5'-O-(3-thiotriphosphate)(GTP-gamma-S) decreased the Ca2+ current amplitude by 36 and 41%, respectively, and induced a biphasic rising phase in the Ca2+ current. Under these conditions, application of 0.1 microM-SOM produced significantly less block of Ca2+ current amplitude (7.1 and 14.7%, respectively) when compared with controls. 7. Internal dialysis with solutions containing 500 microM-guanosine-5'-O-(2-thiodiphosphate)(GDP-beta-S) had no significant effect on either the Ca2+ current amplitude or block produced by 0.1 microM-SOM. 8. Internal dialysis with solutions containing 500 microM-cyclic adenosine 3',5'-monophosphate (cyclic AMP) and 3-isobutyl-1-methylxanthine had no significant effect on either the Ca2+ current block produced by 0.1 microM-SOM or the Ca2+ current amplitude.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Somatostatin blocks a calcium current in rat sympathetic ganglion neurones. 247 36

The ontogeny of somatostatin receptors in the rat brain has been studied by both membrane binding assays and in vitro receptor autoradiographic techniques. High levels of somatostatin binding sites were detected in brain of 15-day-old fetuses (E15). The pharmacological characterization of somatostatin binding sites and the regulatory effect of GTP on somatostatin binding at E15 suggest that somatostatin recognition sites correspond to authentic receptors. The values of maximal binding showed important variations throughout pre- and postnatal development. Globally, a marked increase in the total binding capacity was observed between E15 and postnatal day 8 (P8), with a transient fall at birth and P1. After P8, the concentration of somatostatin receptors progressively decreased and the weaning imposed at P21 accentuated the decline of receptor concentration. Although the density of somatostatin binding sites varied considerably, KD values did not change during brain development. Autoradiographic studies showed marked differences in the distribution of somatostatin receptors during ontogenesis. In the cortex, the cortical plate and the subplate zone appeared to contain high densities of binding sites from E15 to P1. However, the cortical layer which exhibited the higher labelling was the intermediate zone, located just beneath the subplate zone. On the contrary, the germinal epithelium bordering the lateral ventricle appeared virtually devoid of somatostatin binding sites. This laminar distribution of binding sites in the cortex disappeared from P4 to P8, in coincidence with the evolution of the underlying histological organization. At these stages, a homogeneous distribution was observed in almost all cortical layers, contrasting with the distribution of somatostatin receptors in the adult, which was restricted to layers IV-VI. In the cerebellar cortex, autoradiographic labelling was first seen at E15. After birth, the density of somatostatin receptors increased dramatically between P4 and P13, while, at P23, the labelling vanished in most lobes of the cerebellum. Taken together, these results show the early appearance of somatostatin receptors in the rat brain. The high density of somatostatin receptors observed in proliferative or pre-migratory areas suggests that somatostatin may be an important factor involved in the organization of the central nervous system.
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PMID:Ontogeny of somatostatin receptors in the rat brain: biochemical and autoradiographic study. 254 25

Somatostatin has been demonstrated to negatively regulate pancreatic growth in vivo. In this study we used the AR4-2J rat pancreatic acinar tumor cell line to investigate the effect of a stable somatostatin analog, SMS 201-995 (SMS) on cell proliferation. SMS induced an antiproliferative effect on both serum or epidermal growth factor (EGF)-induced cell proliferation; exposure of the cells for 48 h to SMS caused a slight inhibition of serum-induced proliferation (maximal inhibition, 26%) and abolished the growth-promoting effect of EGF. Maximal effect was observed with 10 nM SMS, and half-maximal (IC50) effect with 0.06-0.1 nM SMS. Binding studies with an iodinated derivative of SMS, [125I-Tyr3]SMS, revealed the presence of a single class of high affinity binding sites on AR4-2J plasma membranes with an equilibrium dissociation constant of 0.2 +/- 0.03 nM and a binding site number of 1.1 +/- 0.07 pmol/mg protein. Addition of the nonhydrolyzable GTP analog, guanosine 5-[gamma-thio] triphosphate (GTP gamma S), increased the rate of dissociation of the specifically bound peptide in agreement with the coupling of somatostatin receptors with a GTP-binding regulatory protein. The good agreement between the IC50 for SMS inhibition of cell proliferation and the apparent Kd for binding indicates that the characterized binding sites are the somatostatin receptors that mediate the antiproliferative effect of SMS. When cells were grown in serum-free medium EGF stimulated AR4-2J cell proliferation with half-maximal (ED50) and maximal effects at 0.6 and 10 nM EGF, respectively. This stimulatory effect of EGF was mediated by specific receptors, since binding studies with [125I]EGF indicated that AR4-2J cells contained a single class of EGF receptors (13,000 sites/cell), with an affinity constant for [125I]EGF (Kd = 0.9 +/- 0.09 nM) close to the ED50 for EGF stimulation of cell growth. To examine if SMS-induced growth inhibition involved a cAMP-dependent mechanism we first studied the effect of SMS on cAMP production. SMS had no effect on basal cAMP, but completely inhibited VIP-stimulated cAMP production with an IC50 of 0.2 nM. Pertussis toxin, which is known to abolish the inhibitory effect of somatostatin on adenylate cyclase activity in AR4-2J cells, did not reverse the ability of SMS to inhibit cell proliferation as well as EGF-induced cell proliferation. These data indicate that the antiproliferative effect of SMS does not involve the GTP-binding protein-mediated negative coupling of somatostatin receptors to adenylate cyclase.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Direct inhibitory effects of a somatostatin analog, SMS 201-995, on AR4-2J cell proliferation via pertussis toxin-sensitive guanosine triphosphate-binding protein-independent mechanism. 256 40

The actions of somatostatin and of the phorbol ester 4 beta-phorbol 12-myristate 13-acetate (PMA) were studied in rat insulinoma (RINm5F) cells by electrophysiological and 86Rb+ flux techniques. Both PMA and somatostatin hyperpolarize insulinoma cells by activating ATP-sensitive K+ channels. The presence of intracellular GTP is required for the somatostatin effects. PMA- and somatostatin-induced hyperpolarization and channel activity are inhibited by the sulfonylurea glibenclamide. Glibenclamide-sensitive 86Rb+ efflux from insulinoma cells is stimulated by somatostatin in a dose-dependent manner (half maximal effect at 0.7 nM) and abolished by pertussis toxin pretreatment. Mutual roles of a GTP-binding protein, of protein kinase C, and of cAMP in the regulation of ATP-sensitive K+ channels are discussed.
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PMID:Regulation of ATP-sensitive K+ channels in insulinoma cells: activation by somatostatin and protein kinase C and the role of cAMP. 256 41

Previous studies from this laboratory showed that treatment with 17-beta-estradiol (E2) caused an acquisition of inhibitory effect of somatostatin (SRIF) on prolactin release with an increased number of SRIF-binding sites in the rat anterior pituitary. The aim of this study was to characterize the E2-dependent SRIF receptor in comparison with the E2-independent one, which was expressed in ovariectomized rats. The following observations were obtained: 1) both of the E2-dependent and E2-independent SRIF receptors, measured with 125I-Tyr11-SRIF as a radiolabeled ligand, were enriched in the plasma membrane fraction of the cells, displaying a single class of binding site (E2-dependent: Kd, 32 pM, Bmax, 2.3 pmol/mg protein; E2-independent: Kd, 83 pM, Bmax, 0.26 pmol/mg protein). The ligand binding to both receptors was sensitive to monovalent and divalent cations, and GTP. 2) Among the SRIF analogs tested, the relative potencies of SRIF28 and its analog and cyclosomatostatin compared with SRIF were lower in the E2-dependent receptor than in the E2-independent one. 3) A cross-linking study with N-hydroxysuccinimidyl-4-azido-benzoate revealed that the molecular weight of the cross-linked E2-dependent receptor was approximately 94,000, whereas that of the E2-independent one was 82,000, irrespective of the presence of a reducing reagent. The molecular weight of SRIF receptor from normal male or female rat pituitary was similar to the E2-independent type. 4) Both types of the cross-linked SRIF receptors were solubilized by sucrose monolaurate, adsorbed to a wheat germ agglutinin-agarose column, and eluted with N-acetyl-glucosamine. 5) SRIF inhibited the forskolin-stimulated adenylate cyclase activity in the pituitary membranes from E2-treated rats, but it did not in the E2-depleted membranes. These results demonstrate that there are at least two subtypes of SRIF receptor in the rat anterior pituitary, one of which is exclusively expressed by the treatment with E2, and that these subtypes are distinct with respect to ligand binding specificity, molecular weight, and coupling to adenylate cyclase inhibition.
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PMID:Characterization of 17-beta-estradiol-dependent and -independent somatostatin receptor subtypes in rat anterior pituitary. 256 36

The phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and thyroliberin exerted additive stimulatory effects on prolactin release and synthesis in rat adenoma GH4C1 pituicytes in culture. Both TPA and thyroliberin activated the adenylate cyclase in broken cell membranes. When combined, the secretagogues displayed additive effects. TPA did not alter the time course (time lag) of adenylate cyclase activation by hormones, guanosine 5'-[beta,gamma-imino]triphosphate or forskolin, nor did it affect the enzyme's apparent affinity (basal, 7.2 mM; thyroliberin-enhanced, 2.2 mM) for free Mg2+. The TPA-mediated adenylate cyclase activation was entirely dependent on exogenously added guanosine triphosphate. ED50 (dose yielding half-maximal activation) was 60 microM. Access to free Ca2+ was necessary to express TPA activation of the enzyme, however, the presence of calmodulin was not mandatory. TPA-stimulated adenylate cyclase activity was abolished by the biologically inactive phorbol ester, 4 alpha-phorbol didecanoate, by the protein kinase C inhibitor polymyxin B and by pertussis toxin, while thyroliberin-sensitive adenylate cyclase remained unaffected. Experimental conditions known to translocate protein kinase C to the plasma membrane and without inducing adenylate cyclase desensitization, increased both basal and thyroliberin-stimulated enzyme activities, while absolute TPA-enhanced adenylate cyclase was maintained. Association of extracted GTP-binding inhibitory protein, Gi, from S49 cyc- murine lymphoma cells with GH4C1 cell membranes yielded a reduction of basal and hormone-stimulated adenylate cyclase activities, while net inhibition of the cyclase of somatostatin was dramatically enhanced. However, TPA restored completely basal and hormone-elicited adenylate cyclase activities in the Gi-enriched membranes. Finally, TPA completely abolished the somatostatin-induced inhibition of adenylate cyclase in both hybrid and non-hybrid membranes. These data suggest that, in GH4C1 cells, protein kinase C stimulation by phorbol esters completely inactivates the n alpha i subunit of the inhibitory GTP-binding protein, leaving the n beta subunit functionally intact. It can also be inferred that thyroliberin conveys its main effect on the adenylate cyclase through activation of the stimulatory GTP-binding protein, Gs.
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PMID:Protein kinase C stimulates adenylate cyclase activity in prolactin-secreting rat adenoma (GH4C1) pituicytes by inactivating the inhibitory GTP-binding protein Gi. 256 96

Somatostatin, localized throughout the central and peripheral nervous systems, has been found in neurons of the vagal inhibitory pathway of the heart and has been shown to have negative inotopic effects in cardiac tissue. Using patch clamp techniques we show that somatostatin activates an inwardly rectifying K+ channel in rat atrial cells. Loss of somatostatin-induced K+ channel activity in excised inside-out patches is restored by the addition of GTP to the bath. Pertussis toxin pretreatment blocked GTP-dependent somatostatin activation of the inwardly rectifying K+ channel. This K+ channel has a conductance of 34 pS and a mean open time of approximately 1 ms. It is apparently the same K+ channel activated by muscarinic and adenosine receptors in atrial and cardiac pacemaker cells. Thus, atrial cells have at least three receptors which act via pertussis toxin-sensitive G proteins to activate the same class of K+ channels.
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PMID:Somatostatin activates an inwardly rectifying K+ channel in neonatal rat atrial cells. 257 74

Activation of beta-adrenergic and somatostatin receptors increases and attenuates, respectively, cAMP. We have determined, however, that in enteric endocrine cells beta-adrenergic and somatostatin receptors also regulate Na-H exchange activity, independent of their effects on cAMP. In cells loaded with a pH-sensitive dye, epinephrine, acting at a beta 2-adrenergic receptor induced an alkalinization while somatostatin caused an acidification of intracellular pH (pHi). These pHi changes were dependent on extracellular Na+ and inhibited by amiloride. Forskolin, dibutyryl-cAMP and 8-bromo-cAMP, however, had no effect on pHi. Cholera toxin, while decreasing the EC50 for epinephrine-stimulated increases in cAMP, had no effect on epinephrine-induced alkalinization, suggesting receptor coupling to Na-H exchange was not mediated by a cholera toxin-sensitive stimulatory GTP-binding protein (Gs). Additionally, epinephrine stimulated Na-H exchange in cyc- variants of S49 lymphoma cells, which lack a fundamental Gs. In the presence of pertussis toxin, somatostatin attenuation of cAMP was completely reversed; however, somatostatin inhibition of Na-H exchange was not affected. We suggest that beta-adrenergic and somatostatin receptors regulate Na-H exchange independent of changes in cAMP and possibly independent of GTP-binding proteins previously described as being coupled to these receptors.
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PMID:Beta-adrenergic and somatostatin receptors regulate Na-H exchange independent of cAMP. 257 75

Somatostatin receptors of plasma membranes from beta cells of hamster insulinoma were covalently labelled with 125I-[Leu8,D-Trp22,Tyr25]somatostatin-28 (125I-somatostatin-28) and solubilized with the non-denaturing detergent Triton X-100. Analysis by SDS/PAGE and autoradiography revealed three specific 125I-somatostatin-28 receptor complexes with similar molecular masses (228 kDa, 128 kDa and 45 kDa) to those previously identified [Cotroneo, P., Marie, J.-C. & Rosselin, G. (1988) Eur. J. Biochem. 174, 219-224]. The major labelled complex (128 kDa) was adsorbed to a wheat-germ-agglutinin agarose column and eluted by N-acetylglucosamine. Also, the binding of 125I-somatostatin-28 to plasma membranes was specifically inhibited by the GTP analog, guanosine-5'-O-(3-thiotriphosphate) (GTP[S]) in a dose-dependent manner. Furthermore, when somatostatin-28 receptors were solubilized by Triton X-100 as a reversible complex with 125I-somatostatin-28, GTP[S] specifically dissociated the bound ligand to a larger extent from the soluble receptors than from the plasma-membrane-embedded receptors, the radioactivity remaining bound after 15 min at 37 degrees C being 30% and 83% respectively. After pertussis-toxin-induced [32P]ADP-ribosylation of pancreatic membranes, a 41-kDa [32P]ADP-ribose-labelled inhibitory guanine nucleotide binding protein coeluted with the 128-kDa and 45-kDa receptor complexes. The labelling of both receptor proteins was sensitive to GTP[S]. The labelling of the 228-kDa band was inconsistent. These results support the conclusion that beta cell somatostatin receptors can be solubilized as proteins of 128 kDa and 45 kDa. The major labeled species corresponds to the 128-kDa band and is a glycoprotein. The pancreatic membrane contains a 41-kDa GTP-binding protein that can complex with somatostatin receptors.
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PMID:Solubilization of somatostatin receptors in hamster pancreatic beta cells. Characterization as a glycoprotein interacting with a GTP-binding protein. 257 68

In the present work, we have characterized by film radioautography the effects of divalent cations and guanine nucleotide on specific receptor for somatostatin (SRIF) using 125I-TyrO-DTrp8-SRIF14 (125I-ToD8-SRIF) as a ligand. The experiments were performed on coronal 20-microM-thick sections cut at the level of the amygdala, thus allowing to study binding sites in several regions enriched in binding sites (frontal cortex, hippocampus CA1 and dentate gyrus, habenula, basolateral nucleus of the amygdala). In a preliminary set of experiments using brain cortical membranes it was found that 3 mM Mg2+ ions doubled the specific binding of 125I-ToD8-SRIF. However, Mg2+ enhanced equally by a factor of 3 affinities of high- and low-affinity binding sites as evidenced by SMS 201.995 displacement curves without modifying the ratio between high and low affinity sites. In radioautographic studies while SRIF14 and SRIF28 elicited monophasic displacement curves, SMS 201.995 displaced 125I-ToD8-SRIF binding in a biphasic manner in all regions tested but the baso-lateral nucleus of the amygdala. Radioautographic distribution of 125I-ToD8-SRIF binding sites was identical whether the sections were incubated with MgCl2 or with MnCl2 and almost undetectable in the absence of ions. In all structures investigated increasing concentrations of GTP totally inhibited 125I-ToD8-SRIF binding with an IC50 value of 3 microM. In conclusion, our results demonstrate that 125I-ToD8-SRIF-binding sites in brain occur on two different affinity states as assessed by a displacement curve using endogenous ligands and SMS 201.995. According to the comparable effects of divalent cations and GTP, the two subtypes of 125I-ToD8-SRIF-binding sites discriminated by SMS 201.995 are likely to correspond to interconvertible forms of the same receptor coupled to a G protein-transducing system.
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PMID:Regional distribution of somatostatin receptor affinity states in rat brain: effects of divalent cations and GTP. 257 46

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