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 gene encoding a novel mouse somatostatin receptor termed mSSTR3 was isolated and characterized. The sequence of mSSTR3 shows 46 and 47% identity with mSSTR1 and mSSTR2, respectively. mSSTR3 binds somatostatin-14 and somatostatin-28 with high affinity, but shows very low affinity for the somatostatin analogs MK-678 and SMS-201-995. In addition, mSSTR3 is coupled to pertussis toxin-sensitive G proteins and mediates somatostatin inhibition of forskolin-stimulated and dopamine D1 receptor-stimulated cAMP formation, indicating that it is coupled to adenylylcyclase. The pharmacological properties of mSSTR3 and its ability to couple with adenylylcyclase distinguish SSTR3 from the other cloned somatostatin receptors and indicates that it mediates biological functions different from SSTR1 or SSTR2. In situ hybridization indicates that SSTR3 mRNA is widely distributed in the mouse brain, and its expression in the nucleus of the lateral olfactory tract and in the piriform cortex, the primary olfactory cortex in the rodent brain, suggests that SSTR3 may participate in the processing and modulation of primary sensory information.
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PMID:Cloning of a novel somatostatin receptor, SSTR3, coupled to adenylylcyclase. 132 99

Somatostatin reduces voltage-dependent Ca2+ current (ICa) and intracellular free Ca2+ concentration in the AtT-20/D16-16 pituitary cell line. We tested whether guanine nucleotide-binding proteins (G or N proteins) are involved in the signal transduction mechanism between the somatostatin receptor and voltage-dependent Ca2+ channels. Treatment of the cells with pertussis toxin, which selectively ADP ribosylates the GTP binding proteins Gi and Go and suppresses the ability of Gi to couple inhibitory receptors to adenylate cyclase, abolished the action of somatostatin on both ICa and intracellular free Ca2+. Intracellular application of the nonhydrolyzable guanine nucleotide analog guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]), which irreversibly activates G proteins, changed the somatostatin effect on ICa from a reversible to an irreversible inhibition. Intracellular GTP[gamma S] alone caused a very slowly developing inhibition of ICa. When ICa was inhibited by GTP[gamma S] (alone or with somatostatin), it failed to respond to subsequent applications of somatostatin. The effect of GTP[gamma S] on the inhibition of ICa by somatostatin was not altered by the intracellular application of cAMP and 3-isobutyl-1-methylxanthine. The results suggest that a GTP-binding protein is directly involved in the cAMP-independent receptor-mediated inhibition of voltage-dependent Ca2+ channels.
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PMID:A guanine nucleotide-binding protein mediates the inhibition of voltage-dependent calcium current by somatostatin in a pituitary cell line. 243 11

The human gastric tumoral cell line HGT-1 was previously shown to contain a membrane somatostatin receptor negatively coupled to adenylate cyclase through a pertussis toxin-sensitive inhibitory GTP-binding regulatory protein (Gi) (Reyl-Desmars, F., Laboisse, C., and Lewin, M. J. M. (1986) Regul. Pept. 16, 207-215). In this study, we have solubilized this receptor in a free unoccupied form using Triton X-100 as detergent and [125I-Tyr11]somatostatin-14 to monitor specific binding. Furthermore, we have prepared a monoclonal antibody against a chromatographically enriched soluble receptor fraction and used this antibody (30F3) to immunopurify the receptor in conjunction with Sepharose-somatostatin-14 immunopurification and steric exclusion high pressure liquid chromatography (HPLC). The purified fraction showed 18,600-fold enrichment in terms of specific binding (i.e. from 0.6 +/- 0.05 to 11,300 +/- 830 pmol/mg of protein) and a single dissociation constant (kappa D) of 76 +/- 8 nM. On HPLC, it migrated as a single and symmetric 90-kDa peak. Moreover, after 125I-protein labeling, it gave a single 90-kDa band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography. On the other hand, the 30F3 monoclonal antibody immunoblotted with a single 90-kDa band contained in the HGT-1 cell membrane. We therefore suggest that this antibody is specific to the HGT-1 membrane somatostatin receptor, that this receptor has a molecular mass of 90 kDa, and that we have obtained a homogeneous preparation of nondenatured receptor suitable for further cloning studies.
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PMID:Solubilization and immunopurification of a somatostatin receptor from the human gastric tumoral cell line HGT-1. 257 96

To investigate the mechanism of the suppressive action of somatostatin on gastric acid secretion, we determined the somatostatin binding and adenylate cyclase activity on crude membrane fractions of isolated gastric glands of guinea pigs. The binding studies using 125I-Tyr11 somatostatin showed the presence of somatostatin receptors with a single high affinity on crude membrane fractions. The dissociation constant (KD) for somatostatin was 1.05 +/- 0.13 nM, and the number of binding sites (Bmax) was 6.98 +/- 1.27 fmol/mg protein (mean +/- SE, n = 6). The adenylate cyclase activity was increased by histamine, which was completely inhibited by 10(-3) M cimetidine. Somatostatin non-competitively suppressed the histamine-stimulated adenylate cyclase activity in the presence of guanosine 5'-triphosphate (GTP). These results suggest that somatostatin inhibits histamine-stimulated acid secretion through the inhibition of the adenylate cyclase system, via somatostatin receptor and guanine nucleotide binding protein, which is activated by GTP binding.
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PMID:Somatostatin receptors and the effect of somatostatin on histamine-stimulated adenylate cyclase activity in isolated gastric glands of guinea pigs. 257 63

More insight into the biochemical structure and operation of the somatostatin receptor(s) has been gained in recent years from several approaches. The minimal active structure of the receptor(s) has been identified, and active minisomatostatins have been synthesized. High-affinity binding sites (KDS ranging from 0.1 to 1 nM) have been demonstrated in brain and peripheral organs. In pancreas, stomach, and intestine additional low-affinity sites (or states) have been also suggested Furthermore, cytosolic receptors might be present. Binding affinities of synthetic minisomatostatins, somatostatin-14 and somatostatin-28, show different tissue specificities, suggesting the existence of different receptor subtypes. Two possible interactions of somatostatin with stimulus-secretion coupling in secretory cells have been suggested: a direct activation of the GTP-dependent inhibitory subunit of adenylate cyclase and a distal activation of cytosolic phosphoprotein phosphatases.
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PMID:Somatostatin receptors. 287 5

The beta-adrenergic receptor kinase is a cytosolic enzyme that specifically phosphorylates the agonist-occupied form of the beta-adrenergic receptor (beta AR). Beta AR kinase appears to be translocated from the cytosol to the plasma membrane when kin- S49 lymphoma cells are incubated with either beta-adrenergic agonists or prostaglandin E1, both of which act through receptors which stimulate adenylate cyclase. We report here that brief (approximately 20 min) exposure of wild type S49 lymphoma cells to somatostatin (which inhibits adenylate cyclase) promotes the translocation of beta AR kinase to an extent comparable to that observed in the presence of the beta agonist isoproterenol or prostaglandin E1. Beta AR kinase activity can be measured using either beta AR or rhodopsin, the retinal receptor for light, as a substrate. The translocation process triggered by somatostatin is rapid, reversible, and is associated with somatostatin receptor desensitization. The latter is apparent as an attenuation of the inhibition by somatostatin of forskolin-stimulated adenylate cyclase activity in membranes of S49 cells preincubated in the presence of the peptide. These results strongly suggest that beta AR kinase is able to phosphorylate and desensitize both stimulatory and inhibitory adenylate cyclase-coupled receptors, thus emerging as a general kinase that regulates the function of different receptors in an agonist-specific fashion.
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PMID:Somatostatin induces translocation of the beta-adrenergic receptor kinase and desensitizes somatostatin receptors in S49 lymphoma cells. 288 86

Primary cultures of mouse embryonic neurones from the cerebral cortex and rat pituitary membranes were used to identify and characterize further the somatostatin receptors coupled to an adenylate cyclase and to compare these receptors with specific binding sites for a non-reducible somatostatin analog. 125I-CGP 23996 on both tissues. 125I-CGP 23996 bound specifically to a single population of sites on cortical neurones and pituitary membranes, with a high affinity (Kd = 2.76 and 1.95 nM respectively). The rank order of potency of somatostatin-(1-14) and some analogs (somatostatin-28, [D-Trp8,D-Cys14]somatostatin-(1-14), native CGP) to displace 125I-CGP 23996 from its binding sites was similar on both tissues. Furthermore this rank order was also found identical for the inhibition of adenylate cyclase activity on cortical neuronal and pituitary membranes. Finally a good correlation was found between the order of potencies of somatostatin analogs evaluated from binding experiments and adenylate cyclase assays, suggesting the presence of the same receptor observed under two different affinity states. According to the classification of somatostatin receptors by Tran and his colleagues (1985) these results support the hypothesis that SSA is the somatostatin receptor coupled with an adenylate cyclase.
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PMID:Somatostatin receptors on cortical neurones and adenohypophysis: comparison between specific binding and adenylate cyclase inhibition. 288 38

Somatostatin receptors from a rat pancreatic acinar cell line, AR4-2J, were characterized biochemically, structurally, and functionally. Binding of 125I-[Tyr11]somatostatin to AR4-2J cells was saturable, exhibiting a single class of high-affinity binding sites (Kd = 0.55 +/- 0.06 nM) with a maximal binding capacity of 258 +/- 20 fmol/10(6) cells. Somatostatin receptor structure was analyzed by covalently cross-linking 125I-[Tyr11]somatostatin to its plasma membrane receptors. Gel electrophoresis and autoradiography of cross-linked proteins revealed a peptide (Mr 80,000) containing the somatostatin receptor. Somatostatin inhibited vasoactive intestinal peptide (VIP)-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) formation in a dose-dependent manner. The concentration of somatostatin that caused half-maximal inhibition of cAMP formation (IC50 = 0.4 nM) was close to the receptor affinity for somatostatin. Pertussis toxin pretreatment of AR4-2J cells prevented somatostatin inhibition of VIP-stimulated cAMP formation as well as somatostatin binding. We conclude that AR4-2J cells exhibit functional somatostatin receptors that retain both specificity and affinity of the pancreatic acinar cell somatostatin receptors and act via the pertussis toxin-sensitive guanine nucleotide-binding protein Ni to inhibit adenylate cyclase.
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PMID:Functional somatostatin receptors on a rat pancreatic acinar cell line. 289 95

Somatostatin binding and cross-linking to its receptors on rat cerebrocortical membranes were characterized with [125I-Tyr1]somatostatin-14 and [125I-Leu8, D-Trp22, Tyr25]somatostatin-28. When [125I-Tyr1]somatostatin-14 was cross-linked to its receptors with the photoreactive cross-linker, N-(5-azido-2-nitrobenzoyloxy)succinimide, the hormone was specifically associated with a Mr = 72,000 protein band in the presence or absence of reducing agents. Affinity labeling of the Mr = 72,000 protein band was decreased with increasing concentrations of unlabeled somatostatin-14 and nonhydrolyzable guanine nucleotide analog, guanyl-5'-yl imidodiphosphate (Gpp(NH)p). Pretreatment of cerebrocortical membranes with islet-activating protein resulted in a decrease in subsequent labeled somatostatin-14 binding and affinity-labeling of the protein and abolished an inhibitory effect of somatostatin-14 on vasoactive intestinal peptide-stimulated increase in adenylate cyclase activity. When the affinity-labeled protein was solubilized with Zwittergent 3-12 and adsorbed to wheat germ agglutinin-agarose, it was eluted by N-acetylglucosamine. [125I-Leu8, D-Trp22, Tyr25]somatostatin-28 cross-linking to cerebrocortical and pancreatic membranes with the same photoreactive agent revealed specifically labeled protein bands of a Mr = 74,000 in cerebrocortical membranes and a Mr = 94,000 in pancreatic membranes, respectively. These results suggest that: 1) somatostatin receptor on cerebrocortical membranes is a monomeric glycoprotein with a Mr = 70,000 binding subunit, coupled to guanine nucleotide regulatory protein, and 2) the Mr = 70,000 protein may be a common receptor for somatostatin-28 and somatostatin-14 and is distinct from a common pancreatic type receptor.
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PMID:Somatostatin receptors on rat cerebrocortical membranes. Structural characterization of somatostatin-14 and somatostatin-28 receptors and comparison with pancreatic type receptors. 290 82

The involvement of G proteins in receptor mediated astroglial cAMP formation was studied. Isoproterenol or prostaglandin E2 stimulated adenylate cyclase of primary astroglial cells was inhibited by somatostatin. Preincubation of cells with increasing concentrations of islet activating protein (IAP) diminished somatostatin inhibition of adenylate cyclase. At an IAP concentration of 50 ng/ml somatostatin inhibition was completely abolished. Studies on IAP catalyzed 32P-ADP-ribosylation of astroglial cell particulate material revealed an incorporation of radiolabel into three polypeptides in the molecular weight range of 41,000-39,000 Dalton. Pretreatment of intact cells with IAP reduced radiolabeling of this molecular species in a concentration dependent manner. No further radiolabeling above background level was detectable after pretreatment of cultures with 10 ng IAP/ml or more. At present, the occurrence of at least three IAP substrates (G proteins) does not permit an identification of the somatostatin receptor coupled G protein. Rather, the finding reveals that astrocytes are endowed with multiple variants of GTP binding proteins likely to be coupled to different receptors.
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PMID:Multiple pertussis toxin substrates as candidates for regulatory G proteins of adenylate cyclase coupled to the somatostatin receptor in primary rat astrocytes. 290 73


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