Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 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

Previous studies have shown that at least two subtypes of somatostatin (SRIF) receptors (SRIF1 and SRIF2) are expressed in mammalian cells. SRIF1 receptors have high affinity for MK 678, whereas SRIF2 receptors have no affinity for MK 678 but selectively bind peptides with structures similar to that of CGP 23996. Recently, two SRIF receptor genes have been cloned from human and mouse genomic libraries. In the present study, the pharmacological properties of these two cloned SRIF receptors, expressed in Chinese hamster ovary (CHO) cells, were investigated, to determine whether they have any similarity to the previously described SRIF1 and SRIF2 receptor subtypes. Both cloned receptors could be labeled with 125I-Tyr11-SRIF and exhibited high affinity for SRIF. The SSTR1 receptor could also bind CGP 23996-like compounds but not MK 678. In contrast, the SSTR2 receptor was insensitive to CGP 23996-like compounds but bound MK 678 with high affinity. These findings indicate that the peptide specificities of the cloned SSTR1 and SSTR2 receptors differ from each other. Pretreatment of CHO cells expressing the two cloned SRIF receptors with SRIF abolished high affinity agonist binding to the cloned SSTR2 receptor but not the cloned SSTR1 receptor. Agonist binding to SSTR1 receptors was not significantly affected by guanosine-5'-)-(3-thiotriphosphate) or pertussis toxin pretreatment, whereas agonist binding to SSTR2 receptors was inhibited by both treatments. These findings suggest that SSTR2 receptors can be regulated and they associate with pertussis toxin-sensitive guanine nucleotide-binding proteins, whereas SSTR1 receptors do not. SRIF is a potent inhibitor of adenylyl cyclase activity in mammalian cells. However, neither the cloned SSTR2 nor SSTR1 receptor mediated SRIF inhibition of adenylyl cyclase activity in stably transformed CHO cells or COS-1 cells transiently expressing the cloned receptors, suggesting that neither cloned receptor couples to adenylyl cyclase. The results of these studies indicate that the two cloned SRIF receptors have different pharmacological properties. The characteristics of the cloned SSTR2 receptor are similar to those of the previously described SRIF1 receptor, and the characteristics of the cloned SSTR1 receptor are similar to those of the previously described SRIF2 receptor.
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PMID:Pharmacological properties of two cloned somatostatin receptors. 135 50

Recent studies in a cultured model of the intestinal epithelium (HT-29cl.19A) have shown that somatostatin-14 (SS-14) inhibits the Cl- secretory process by acting at multiple G protein-dependent sites. These actions may underlie the antidiarrheal properties of SS peptides. This study has investigated the expression of specific SS receptor subtypes (SSTR) in HT-29cl.19A and examined their role in mediating SS antisecretory actions. Two predominant SSTR, SSTR1 and SSTR2, were identified by reverse transcriptase-polymerase chain reaction (RT-PCR) of mRNA from polarized HT-29cl.19A monolayers. Receptor binding studies showed evidence of two distinct populations of binding sites consistent with the known properties of SSTR1 and SSTR2. The role of SSTR in inhibition of secretion was investigated by comparing the effectiveness of native and synthetic SS peptides on adenosine 3',5'-cyclic monophosphate (cAMP)-dependent Cl- secretion. Secretion stimulated by the receptor-mediated agonist prostaglandin E2 (PGE2) was inhibited > 70% by SS-14 with a 50% effective concentration (EC50) of 32 nM. In contrast, SMS-201-995 (SMS) and RC-160 exhibited little or no antisecretory activity (maximum inhibition of 15 +/- 1.9 and 2.8 +/- 1.9%, respectively, at 100 microM; EC50 > 1.5 microM). Similar effects on PGE2-stimulated cAMP accumulation were also observed. SS-14, but not SMS, also inhibited secretion stimulated by dibutyryl cAMP, which acts independently of changes in cellular cAMP. Pretreatment with pertussis toxin reversed the antisecretory effects of SS peptides.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression of somatostatin receptor genes and their role in inhibiting Cl- secretion in HT-29cl.19A colonocytes. 749 65

The signal transduction pathways of a cloned human somatostatin receptor subtype, SSTR1, have been investigated in CHO cells stably expressing this receptor. In SSTR1-expressing CHO cells, somatostatin-14 inhibits forskolin-stimulated cAMP formation in a dose-dependent manner with an ED50 of 1.0 x 10(-9) M. Somatostatin-14 also stimulates inositol 1,4,5-trisphosphate formation in a dose-dependent manner with an ED50 of 4.0 x 10(-8) M. Somatostatin-14 inhibitory action on adenylyl cyclase and stimulatory action on inositol 1,4,5-trisphosphate formation are both blocked by pertussis toxin, indicating that these effects of SSTR1 are mediated by pertussis toxin-sensitive G protein(s). Antiserum against Gi alpha 3 blocked the inhibitory effects of somatostatin-14 on forskolin-stimulated adenylyl cyclase, but antiserum against Gi alpha 1/Gi alpha 2 did not, indicating that Gi alpha 3 dominantly couples SSTR1 to adenylyl cyclase. These results demonstrate that SSTR1 can be coupled to different signaling pathways to exert multiple biological effects, one of which is mediated by Gi alpha 3.
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PMID:Multiple effector coupling of somatostatin receptor subtype SSTR1. 752 97

The diverse biological effects of somatostatin (SST) are mediated through a family of G protein coupled receptors of which 5 members have been recently identified by molecular cloning. This review focuses on the molecular biology, pharmacology, expression, and function of these receptors with particular emphasis on the human (h) homologs. hSSTRs are encoded by a family of 5 genes which map to separate chromosomes and which, with one exception, are intronless. SSTR2 gives rise to spliced variants, SSTR2A and 2B. hSSTR1-4 display weak selectivity for SST-14 binding whereas hSSTR5 is SST-28 selective. Based on structural similarity and reactivity for octapeptide and hexapeptide SST analogs, hSSTR2,3, and 5 belong to a similar SSTR subclass. hSSTR1 and 4 react poorly with these analogs and belong to a separate subclass. All 5 hSSTRs are functionally coupled to inhibition of adenylyl cyclase via pertussis toxin sensitive GTP binding proteins. Some of the subtypes are also coupled to tyrosine phosphatase (SSTR1,2), Ca2+ channels (SSTR2), Na+/H+ exchanger (SSTR1), PLA-2 (SSTR4), and MAP kinase (SSTR4). mRNA for SSTR1-5 is widely expressed in brain and peripheral organs and displays an overlapping but characteristic pattern that is subtype-selective, and tissue- and species-specific. Pituitary and islet tumors express several SSTR genes suggesting that multiple SSTR subtypes are coexpressed in the same cell. Structure-function studies indicate that the core residues in SST-14 ligand Phe6-Phe11 dock within a ligand binding pocket located in TMDs 3-7 which is lined by hydrophobic and charged amino acid residues.
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PMID:The somatostatin receptor family. 767 17

Somatostatin receptors are abundantly expressed on a variety of human endocrine and epithelial tumors. The ability of these receptors to couple to effector pathways that inhibit the growth of these tumor cells has prompted the use of somatostatin agonists in the treatment of human neoplasms. It has been demonstrated that somatostatin stimulates a phosphotyrosine phosphatase in human tumor cells through a receptor-mediated process. This stimulation may counteract the growth-promoting properties of growth factors and the receptor tyrosine kinases that they activate. The recent cloning and characterization of distinct somatostatin receptor subtypes raise the possibility that different receptor subtypes mediate distinct effector pathways. To determine whether cloned somatostatin receptors could mediate coupling to phosphotyrosine phosphotyrosine phosphatase activity, we examined phosphatase activity after somatotostatin activation of the rat somatostatin receptors SSTR1 and SSTR2 after their stable expression in heterologous Chinese Hamster Ovary (CHO-K1) cells. We found that stimulation of SSTR1 cells was capable of increasing phosphotyrosine phosphatase activity, despite the coupling of both receptors to the inhibition of adenylyl cyclase in these cells. This activation was characterized by an EC50 of 70 nM and was sensitive to pertussis toxin. In addition, we demonstrate that activation of phosphotyrosine phosphatase activity in pituitary cell lines correlates with the endogenous expression of the SSTR1 gene within these cells.
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PMID:The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells. 785 46

Recent reports have suggested that only some of the cloned somatostatin receptors (SSTRs) are coupled to adenylyl cyclase. These studies have used both stable and transiently transfected cells or cells lacking appropriate Gi alpha and are controversial. To investigate SSTR signalling mechanisms, we have established stably transfected CHO-K1 cells expressing human genes for SSTR1-5. The effect of 0.1-100 nM SST-14 and SST-28 on forskolin (1 microM) stimulated cAMP accumulation was determined and compared to their receptor binding affinities. The 5 expressed hSSTRs bound SST-14 and SST-28 with high affinity (IC50 1.1-2.1 nM for SST-14; IC50 0.25-5.4 nM for SST-28). hSSTR1-4 bound SST-14 > SST-28 whereas hSSTR5 bound SST-28 > SST-14. Radioligand binding to hSSTR1-5 was significantly inhibited by GTP, GTP gamma S and pertussis toxin. Both SST-14 and SST-28 inhibited forskolin-induced cAMP stimulation with ED50 values which paralleled their binding affinities for the individual hSSTR subtypes. These results demonstrate that all 5 human SSTRs are functionally coupled to inhibition of adenylyl cyclase in CHO-K1 cells via pertussis toxin sensitive G proteins.
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PMID:All five cloned human somatostatin receptors (hSSTR1-5) are functionally coupled to adenylyl cyclase. 790 65

Somatostatin exerts multiple effects throughout the body by binding to specific somatostatin receptors. Two classes of somatostatin receptors, SRIF1 and SRIF2, have been distinguished biochemically and pharmacologically. Two cDNAs have been recently isolated that encode somatostatin receptors 1 and 2 (SSTR1 and SSTR2, respectively). The pharmacological characteristics of receptors expressing these cDNAs resemble those of the SRIF2 and SRIF1 classes of somatostatin receptors, respectively. We stably expressed the rat homologs of both receptors in Chinese hamster ovary (CHO) cells (type K1). These transfected cell lines recognized the endogenous ligands SS14 and SS28 with high affinity, whereas the synthetic analog MK678 identified only SSTR2. In preparations of CHO-SSTR1 or CHO-SSTR2 cells, SS14 and SS28 inhibited forskolin-stimulated adenylyl cyclase activity by approximately 35%, with ED50 values in the nanomolar range. The adenylyl cyclase inhibition was dependent upon the guanine nucleotide GTP and could be ablated with pertussis toxin preincubation. The present data indicate that SSTR1 and SSTR2 are coupled to inhibition of adenylyl cyclase via pertussis toxin- sensitive G-proteins.
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PMID:The somatostatin receptors SSTR1 and SSTR2 are coupled to inhibition of adenylyl cyclase in Chinese hamster ovary cells via pertussis toxin-sensitive pathways. 790 16

COS-7 cells were transfected with human somatostatin (SRIF) receptor type 1 and 2 (human SSTR1 and SSTR2, respectively) cDNAs. In human SSTR2-expressing cells, SRIF not only inhibited forskolin-induced cAMP accumulation but also stimulated phospholipase C and Ca2+ mobilization. While the inhibition of cAMP accumulation was completely reversed by pertussis toxin (PTX) treatment of the cells, SRIF-induced activation of phospholipase C and Ca2+ mobilization was partially but not completely inhibited by the toxin treatment. In human SSTR1-expressing cells, however, SRIF induced only slight inhibition of cAMP accumulation and stimulation of phospholipase C-Ca2+ system. We conclude that the transfected SSTR2 can couple to phospholipase C as well as adenylate cyclase in a stimulatory and inhibitory manner, respectively. Both PTX-sensitive and -insensitive GTP-binding proteins may be involved in the SSTR2 signal transduction mechanisms.
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PMID:Transfected human somatostatin receptor type 2, SSTR2, not only inhibits adenylate cyclase but also stimulates phospholipase C and Ca2+ mobilization. 791 18

Somatostatin has been shown to exert diverse biological effects in various tissues. Recently, the human genes encoding five subtypes of somatostatin receptor (SSTR1-SSTR5) were cloned. Among these subtypes SSTR2 is present in many endocrine tumors as well as normal tissues and may mediate the effects of somatostatin analog, SMS201-995. In this study, we have investigated the intracellular effect of SSTR2 stably expressed in Chinese hamster ovary cells. Somatostatin-14 does not affect the forskolin stimulated cAMP formation when human SSTR2 is expressed in CHO cells, which lack internal Gi alpha 1 protein. However, somatostatin-14 inhibits the adenylyl cyclase in a dose dependent and pertussis toxin-sensitive manner when human SSTR2 is co-expressed with Gi alpha 1 in CHO cells. These results indicate that human SSTR2 is functionally coupled to Gi alpha 1 protein but not to Gi alpha 2 or Gi alpha 3 when expressed in CHO cells.
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PMID:Human somatostatin receptor, SSTR2, is coupled to adenylyl cyclase in the presence of Gi alpha 1 protein. 791 78


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