Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of somatostatin analogues RC-160 and SMS-201-995 on tyrosine phosphatase and cell proliferation were investigated in COS-7 and NIH 3T3 cells expressing human somatostatin receptor subtype 1 or 2 (SSTR1 or SSTR2). Binding experiments were performed on membranes from COS-7 cells expressing human SSTR1 or SSTR2 using 125I-labeled [Tyr11]S-14 or [Tyr3]SMS-201-995, respectively. The somatostatin analogues RC-160 and SMS-201-995 exhibited low affinity for SSTR1 (IC50 of 0.43 and 1.5 microM, respectively) and high affinity for SSTR2 (IC50 of 0.27 and 0.19 nM). Addition of these analogues to cells expressing either SSTR1 or SSTR2 did not result in an inhibition of adenylate cyclase activity. In SSTR2-expressing cells, both analogues induced a rapid stimulation of a tyrosine phosphatase activity (EC50: RC-160, 2 pM; SMS-201-995, 6 pM) and an inhibition of serum-stimulated proliferation (EC50: RC-160, 6.3 pM; SMS-201-995, 12 pM). In SSTR1-expressing cells, only RC-160 induced stimulation of a tyrosine phosphatase activity. Both analogues caused an inhibition of cell proliferation at a concentration higher than 10 nM in accordance with their affinities for the SSTR1 receptor subtype. A good correlation between the affinities of RC-160 and SMS-201-995 for each receptor subtype and their potencies to inhibit cell proliferation suggests the involvement of these receptors in cell growth regulation. Tyrosine phosphatase was stimulated by both these analogues in SSTR2 and by RC-160 in SSTR1 at affinities similar to their ability to inhibit growth and bind to receptors, implicating tyrosine phosphatase as a transducer of the growth inhibition signal. We also found that mRNAs of receptor subtypes were variably expressed in different pancreatic and colon cancer cell lines, indicating the necessity of a precise analysis of receptor subtypes in target tissues before therapy with analogues.
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PMID:Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2. 790 95

We transfected the COS-7 cells with cDNAs encoding different human somatostatin receptor (hSSTR) subtypes, and found that hSSTR subtypes mediate not only the inhibition of forskolin-induced cAMP accumulation but also the stimulation of phospholipase C (PLC) and Ca2+ mobilization. Activation of PLC by 1 microM somatostatin (SRIF) was in the order of: hSSTR5 > hSSTR2 > hSSTR3 > hSSTR4 >> hSSTR1. Pertussis toxin (PTX) treatment completely or partially reversed the PLC activation. 1 nM SRIF was equally effective for adenylate cyclase (AC) inhibition in a PTX-sensitive manner, in all the cells expressing different hSSTRs, except for hSSTR1. Nevertheless, SRIF stimulated AC even in the presence of forskolin at higher doses of SRIF in PTX-treated hSSTR5-expressing cells. We conclude that the cloned hSSTRs differentially couple to PTX-sensitive and -insensitive G-proteins to modulate PLC, Ca2+ mobilization and AC.
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PMID:Phospholipase C activation and Ca2+ mobilization by cloned human somatostatin receptor subtypes 1-5, in transfected COS-7 cells. 803 40

The prolactin secreting rat pituitary tumor cell line, GH3, expresses high affinity receptors for both vasoactive intestinal peptide (VIP) and somatostatin (SS14). VIP induces prolactin secretion by GH3 cells, an action which is antagonized by SS14. This in vitro model was used to examine the mechanism of action of two synthetic somatostatin analogs, D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-OH (octreotide; SMS 201-995) and cyclo(aminoheptanoyl-Phe-D-Trp-Lys-Thr (benzyl)) (cyclic pentapeptide; CPP). Octreotide and CPP bind to the pituitary somatostatin receptor with lower affinity than does SS14 (KD = 1.3 +/- 1.1; 80 +/- 29; 211 +/- 107 nM for SS14, octreotide and CPP, respectively). SS14 and octreotide were equally effective as inhibitors of VIP-mediated accumulation of cAMP (40% and 45% inhibition, respectively, P < 0.01). SS14 and octreotide also inhibited forskolin-mediated accumulation of cAMP (42% and 40% inhibition of cAMP production, respectively; P < 0.01). The inhibitory action of somatostatin and octreotide on both VIP- and forskolin-mediated cAMP accumulation was blocked by pre-treatment of GH3 cells with pertussis toxin (P < 0.001). Neither SS14 nor octreotide affects the apparent affinity of VIP for its specific receptors on GH3 cells; thus, the inhibitory action of SS14 and octreotide appears to be mediated at the locus of the G-protein-adenylate cyclase complex. In contrast, CPP inhibited VIP-mediated cAMP accumulation slightly, but had no effect on forskolin-mediated cAMP production. Pertussis toxin did not attenuate CPP affects on VIP-mediated cAMP accumulation. However, pre-incubation of GH3 cells with CPP decreased the apparent affinity of receptors for VIP, suggesting that effects of CPP are attributable to interference with VIP binding rather than inhibition at the G-protein-adenylate cyclase complex.
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PMID:Mechanisms of action of long-acting analogs of somatostatin. 809 91

5'-(N-ethylcarboxamido)-adenosine (NECA) and N-[(R)-(phenylisopropyl)]-adenosine (PIA) were incubated in an adenylate cyclase assay of a particulate fraction of caudate-putamen tissue of the rat in order to examine the effect of somatostatin on adenosine receptors coupled adenylate cyclase subunits in vitro. Somatostatin was able to inhibit the enhancement of cyclic AMP formation induced by NECA in the presence of the hydrolysable guanine nucleotide guanosine-triphosphate. The adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine as well as the somatostatin receptor antagonist cyclo (7-aminoheptanoyl-Phe-D-Trp-Lys-O-benzyl-Thr) did not influence somatostatin induced inhibition of NECA-activated adenylate cyclase. Somatostatin did not modulate the effect mediated by the A-1 adenosine receptor agonist PIA. Both pertussis toxin and cholera toxin activated striatal adenylate cyclase acting on the guanine nucleotide regulatory subunit of the enzyme. The stimulation induced by pertussis toxin was antagonized by somatostatin, while in presence of cholera toxin somatostatin enhanced cyclic AMP formation. These results suggest that somatostatin acts through a stimulatory as well as an inhibitory guanine nucleotide regulatory protein subtype to affect probably postsynaptic A-2 adenosine receptor coupled adenylate cyclase activity.
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PMID:Somatostatin modulation of adenosine receptor coupled G-protein subunits in the caudate nucleus of the rat. 810 Sep 88

Somatostatin has a modulatory role in regulating the membrane conductance in hippocampal neurons. To examine the signal transducing molecules involved in this process, we isolated the cDNA encoding the dominant rat hippocampal somatostatin receptor, SSTR4. Distribution of SSTR4 in the adult central nervous system was restricted to the hippocampus, cerebral cortex, striatum, hypothalamus, and thalamus, as determined by Northern blot analysis and in situ hybridization. In SSTR4-expressing Chinese hamster ovary cells, SSTR4 was functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade, with similar ED50 values. All of these pathways, including both MAP kinase kinase and MAP kinase activation, were completely blocked by pretreatment with pertussis toxin. On the other hand, neither inositol 1,4,5-trisphosphate synthesis nor intracellular Ca2+ mobilization was induced upon SSTR4 stimulation. These data indicate that the hippocampal functions of somatostatin might be mediated through diverse but selective second messenger systems activated via SSTR4 and reveal an unsuspected coupling of a neuronal SSTR subtype to a mitogenic signaling pathway. SSTR4, in addition, provides a useful system to study the Ca(2+)-independent, Gi-dependent (pertussis toxin-sensitive) pathway of MAP kinase activation.
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PMID:Functional coupling of SSTR4, a major hippocampal somatostatin receptor, to adenylate cyclase inhibition, arachidonate release and activation of the mitogen-activated protein kinase cascade. 817 84

Effector coupling of somatostatin receptor subtypes sst1 and sst2 was examined in a reconstituted system. Forskolin-stimulated cyclic adenosine monophosphate (cAMP) formation was inhibited 66% by somatostatin (SRIF-14) in CHO cells expressing somatostatin receptor 1(sst1) (CHO-SR1), but not sst2, in a dose-dependent manner with an ED50 of 1 x 10(-9) mol/L SRIF-14. The inhibition was blocked by pertussis toxin (PTX), indicating that sst1 is coupled to adenylyl cyclase via PTX-sensitive Gi protein. In CHO cells, Gi alpha 2 and Gi alpha 3 mRNAs were detected. In adenylyl cyclase assays, 1 mumol/L SRIF-14 caused a 16% inhibition of forskolin-stimulated adenyly cyclase activity. Preincubation with Gi alpha 3, but not Gi alpha 1/Gi alpha 2, antiserum blocked this inhibition. By contrast, sst2 is coupled to adenylyl cyclase via Gi alpha 1. In cells expressing sst2 with Gi alpha 1(CHO-SR2G1), SRIF-14 significantly inhibited forskolin-stimulated cAMP formation by 53% and with an ED50 at 4 x 10(-9)mmol/L SRIF-14, which was completely blocked by PTX; ED50 values for sst1 and sst2 agree with the IC50 values in binding assays. In CHO-SR1, the rank of potency of agonists affecting adenyl cyclase was SRIF-14 = SRIF-28 > RC 160 > SMS 201-995. In CHO-SR2G1, the rank was RC-160 > SRIF-14 = SRIF-28 > SMS 201-995.
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PMID:Effector coupling of somatostatin receptor subtypes on human endocrine tumors. 876 78

Many important advances in our understanding of the growth hormone (GH) axis have occurred during the last decade. A number of neurotransmitters and neuropeptides are implicated in the control of growth hormone-releasing hormone (GHRH) and somatostatin release; however, the role of many of these, such as serotonin, gamma-aminobutyric acid and dopamine, is still a matter of discussion. As a newly isolated hypothalamic peptide with a possible role in the control of GH secretion, pituitary adenylate cyclase activating peptide has received considerable attention. Synthetic hexapeptides that stimulate GH release (GH-releasing peptides 1, 2 and 6) have been identified. Pituitary-specific transcription factors involved in the expression of the GH gene have been identified, the GHRH receptor gene has been cloned, as well as a number of somatostatin receptor genes, and advances in our understanding of the insulin-like growth factor-binding proteins, and growth hormone-binding proteins have been made.
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PMID:The growth hormone axis: control and effects. 880 20

The study of the five somatostatin receptor subtypes (SSTx, where x is the subtype number) has been hampered by the lack of high affinity antagonists. Potent and selective antagonists would increase our understanding of SST structure, function, and regulation. In this study, the identification of novel disulfide-linked cyclic octapeptide antagonists of somatostatin is described. The antagonists contain a core structure of a DL-cysteine pair at positions 2 and 7 of the peptides. Substitution of a D-cysteine at position 2 with an L-cysteine converts the full antagonist into a full agonist. All somatostatin receptor subtypes are coupled to inhibition of adenylate cyclase. The functional properties of these peptides have been determined in radioligand binding assays, in functional coupling of the SST2 subtype to yeast pheromone response pathway, and in cAMP accumulations. One peptide antagonist [Ac-4-NO2-Phe-c(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)-D-Tyr-NH2] displays a binding affinity to SST2 comparable with that observed for the native hormone (Ki = 0.2 nM) and reverses somatostatin-mediated inhibition of cAMP accumulation in rat somatomammotroph GH4C1 cells, cells transfected with the SST2 and SST5 subtypes, as well as somatostatin-stimulated growth of yeast cells expressing the SST2 subtype. This class of somatostatin antagonists, which are the first to be described, should be useful for determination of somatostatin's diverse functions in vivo and in vitro.
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PMID:Identification and characterization of novel somatostatin antagonists. 886 14

Somatostatin analogues are in clinical use for the diagnosis and treatment of several oncological indications, namely pituitary adenomas and endocrine gastrointestinal tumors. In addition for a variety of malignancies their potential value is being studied. It has been speculated that somatostatin plays a role in the homeostasis of gliomas, and that gliomas could be susceptible to antiproliferative effects of somatostatin analogues. These assumptions were tested in 20 human cell lines derived from malignant gliomas and 4 glioblastoma tissue specimens, which were analyzed for their expression of the five known somatostatin receptor genes (SSTR1-5) and for the receptor function. Using semiquantitative PCR techniques, SSTR2 transcripts were found in all 20 cell lines and 4 glioblastomas, SSTR1 transcripts were detected in 9 cell lines and 4 glioblastomas, and SSTR3 transcripts were noted in 7 cell lines and 1 glioblastoma. SSTR4 and SSTR5 transcripts were only rarely detected. Gene expression profiles in glioblastoma tissue specimens resembled those of the cell lines in quality as well as quantity, with average transcript levels being highest for the SSTR2, followed by SSTR1 and SSTR3. However, when compared to GH3 anterior pituitary tumor cells, the relative amounts of PCR amplified DNA fragments were found to be at least 120 fold lower in glioblastoma cell lines and tumor specimens. Binding studies indicated that glioblastoma derived cells contained only minute amounts of SSTRs. No inhibition of proliferation was observed when 10 selected cell lines were incubated with somatostatin-14 (SST-14) or octreotide (SMS 201-995) at concentrations ranging from 10(-9) M to 10(-6) M, however, the proliferation of two cell lines was weakly stimulated after 6 days of incubation with 10(-6) M octreotide. The activity of adenylate cyclase, stimulated by forskolin, was inhibited by maximally 25% at 10(-6) M SST-14 or octreotide in one of 5 selected glioblastoma cell lines. Somatostatin peptides do not seem to exert anti-proliferative effects on glioblastoma cells and therefore appear to be of no obvious value for glioblastoma therapy. Most likely the amount of cell surface SSTRs is not sufficient to mediate antiproliferative effects. Since it has been described that SSTRs are detectable on most differentiated gliomas as well as astrocytes, it may be speculated that SSTRs may be relevant only in the context of well differentiated cellular programs but lose their significance with progressive dedifferentiation.
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PMID:Somatostatin and somatostatin receptors in the diagnosis and treatment of gliomas. 944 32

A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 microgram/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054, 522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.
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PMID:Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2. 972 91


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