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)

In this study, dispersed rat pancreatic acini exhibited secretin subsensitivity in their capacity to release amylase after preexposure to increasing concentrations of the muscarinic cholinergic agonist carbamylcholine. The present study also explores the potential mechanisms involved in this cellular desensitization phenomenon. Secretin subsensitivity of pancreatic acini pre-exposed to 10(-4) M carbamylcholine was observed only at secretin concentrations above 10(-8) M. The desensitized cells had not recovered 3 h after the cholinergic agonist exposure. In these acini, the adenylate cyclase pathway remained unaltered because cholera toxin, forskolin, and 8-Br-cAMP still induced weak, but normal, amylase release when compared with control acini. In vivo administration of pertussis toxin failed to protect the dispersed pancreatic acini against carbamylcholine-induced secretin subsensitivity. Moreover, cAMP production by these acini in response to secretin, cholera toxin, and forskolin was similar to that observed in control acini. Secretin stimulation of inositol phosphate (InsP1, InsP2, InsP3) production after carbamylcholine pre-exposure remained equivalent to that observed in acini that had never been exposed to the cholinergic agonist. Thus, after muscarinic cholinergic agonist exposure, pancreatic acini showed secretin subsensitivity in their capacity to release enzyme. This phenomenon appears to result from modifications at post-second messenger loci.
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PMID:Muscarinic cholinergic induced secretin subsensitivity in rat isolated pancreatic acini. Effects on amylase release, cyclic adenosine monophosphate and inositol phosphate formation. 247 85

We examined the inhibitory effect of somatostatin on pepsinogen secretion using isolated rat gastric chief cells. Secretin and forskolin significantly increased not only pepsinogen secretion from chief cells but also cellular cAMP accumulation in a dose-dependent fashion. Somatostatin significantly inhibited secretin- and forskolin-induced pepsinogen secretion and secretin-induced cellular cAMP accumulation. However, forskolin-induced cellular cAMP accumulation was not inhibited by somatostatin. The inhibitory effect of somatostatin on secretin-induced pepsinogen secretion was abolished by pretreatment with pertussis toxin, but inhibition of forskolin-, carbachol- and cholecystokinin octapeptide-induced pepsinogen secretion was not. These results suggest that somatostatin inhibits pepsinogen secretion in two ways, one is closely related to the pertussis toxin-sensitive G-protein and the other is not determined.
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PMID:Inhibitory action of somatostatin on cAMP dependent pepsinogen secretion from rat gastric chief cells: involvement of pertussis toxin-sensitive G-protein. 791 4

Nerve fibers containing bombesin (BB)/gastrin-releasing polypeptide (GRP), pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), or galanin are known to innervate the mucosa of the upper small intestine. Both BB/GRP and PACAP have been shown to elicit secretin secretion in vivo. We studied whether the above-mentioned neuropeptides can act directly on secretin-producing cells, including the murine neuroendocrine cell line STC-1 and a secretin cell-enriched preparation isolated from rat upper small intestinal mucosa. Secretin release from both cell types was stimulated by various agents known to elicit secretin release and by the neuropeptides BB, GRP, and PACAP, suggesting a comparable response between the two cell preparations. The effects of neuropeptides were further studied in STC-1 cells. BB, GRP, and PACAP stimulated secretin release time and concentration dependently. VIP also stimulated secretin release concentration dependently. Stimulation by BB/GRP or PACAP was accompanied by elevation of inositol-1,4,5-trisphosphate (IP3) or cAMP, respectively. The stimulatory effect of PACAP on secretin release was synergistically enhanced by BB without any synergistic increase in IP3 or cAMP production, suggesting cross talk between different signal transduction pathways downstream of the production of these two second messengers. The L-type Ca2+ channel blocker diltiazem (10 microM) and the Ca2+ chelator EGTA (1 mM) significantly inhibited BB-stimulated secretin release by 64% and 59%, respectively, and inhibited PACAP-stimulated release by 75% and 55%, respectively. The protein kinase A-specific inhibitor Rp-cAMPS (100 microM) also inhibited both BB- and PACAP-stimulated secretin release by 30% and 62%, respectively. Galanin inhibited BB- and PACAP-stimulated secretin release and production of second messengers in a concentration-dependent and pertussis toxin-sensitive manner. These results suggested that the neuropeptides BB/GRP, PACAP, VIP, and galanin can modulate secretin release in secretin-producing cells and that STC-1 cells can serve as a useful model for studying the cellular mechanism of secretin secretion elicited by luminal secretagogues and neuropeptides.
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PMID:Modulation of secretin release by neuropeptides in secretin-producing cells. 968 45

G protein-coupled receptors initiate signaling cascades after associating with heterotrimeric G proteins. This is typically initiated by agonist binding, but can also occur spontaneously, particularly in receptors bearing distinct missense mutations. Two such mutations in the parathyroid hormone receptor are associated with constitutive activity, manifesting clinically as Jansen's metaphyseal chondroplasia. We introduce analogous mutations separately and together into the secretin receptor to explore their impact on another family member. Constructs were expressed transiently in COS cells, and had binding and signaling (cAMP generation) studied. Each construct was processed appropriately to lead to cell surface expression and signaling. Secretin bound to the wild-type receptor with two affinity states recognized, 1% of sites in the high affinity state (Ki = 0.5 +/- 0.1 nM) and 99% in the low affinity state (Ki = 23 +/- 3 nM). Mutant receptor binding best fit a single affinity state, having values for Ki of 5 +/- 1 nM (H156R), 8 +/- 1 nM (T322P) and 6 +/- 1 nM (H156R/T322P), with each of these demonstrating a shift to higher affinity than the predominent low affinity state of the wild-type receptor. Each mutant receptor expressed small to moderate constitutive activity, with basal levels of cAMP activity greater than control (P < .01): H156R, 1.4-fold; T322P, 4.5-fold and H156R/T322P, 6.8-fold. The level of basal activity of even the most active construct was only 15% of the maximal response of wild-type receptor. Although each of the single site mutants responded to secretin by increasing their cAMP levels in a concentration-dependent manner, the dual mutant decreased its cAMP in response to hormone (EC50 = 13 nM). Thus, a natural agonist had become an inverse agonist at this unique construct. Because this could reflect reduced normal coupling with Gs or increased aberrant coupling with Gi, the mechanism was further explored using pertussis toxin and a stable analogue of GTP. Although ligand-binding determinants were retained in the dual receptor mutant, the conformation of this receptor upon secretin binding effected a reduction in its basal coupling with Gs, thereby resulting in inverse agonism.
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PMID:Protean effects of a natural peptide agonist of the G protein-coupled secretin receptor demonstrated by receptor mutagenesis. 969 8

Secretin plays a key role in the regulation of normal cholangiocyte physiology via secretin receptor (SCTR). SCTR expression is upregulated during extrahepatic cholestasis induced by bile duct ligation and closely associated with cholangiocyte proliferative responses. Although well studied in normal cholangiocytes, the role of secretin and the expression of SCTR in the regulation of cholangiocarcinoma proliferation are unknown. In vitro, secretin (10(-7) M) displayed differential effects on normal cholangiocyte [H-69 and human intrahepatic biliary epithelial cell line (HIBEpiC)] and cholangiocarcinoma (Mz-ChA-1, HuH-28, TFK-1, SG231, CCLP1 and HuCC-T1) cell lines as such secretin is mitogenic for normal cholangiocytes and antiproliferative for cholangiocarcinoma. As expected in normal cholangiocytes (HIBEpiC), secretin increased intracellular cyclic adenosine monophosphate (cAMP) levels. However, the effect of secretin on intracellular cAMP levels was suppressed in Mz-ChA-1 cells. Secretin-stimulated intracellular cAMP levels in Mz-ChA-1 were restored by pretreatment with pertussis toxin, suggesting that the receptor coupled to Galpha(i) rather than Galpha(s). SCTR expression was found to be downregulated in 4 of the 6 cholangiocarcinoma cell lines evaluated and in human cholangiocarcinoma biopsy samples. In vivo, secretin significantly inhibited the tumor size and more than doubled tumor latency, which was associated with a decrease in proliferating cell nuclear antigen and an increase in cleaved-caspase 3 expression levels. Our results demonstrate that secretin and/or the modulation of SCTR expression might have potential as a therapeutic tool in the treatment of cholangiocarcinoma.
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PMID:Secretin inhibits cholangiocarcinoma growth via dysregulation of the cAMP-dependent signaling mechanisms of secretin receptor. 1990 46