Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Little experimental evidence has been reported for diverse signaling via 5-hydroxytryptamine (5-HT)1A receptors despite the fact that agonists seem to be more efficacious at dorsal raphe somatodendritic 5-HT1A autoreceptors than at postsynaptic 5-HT1A receptors. The present study investigated Ca2+ responses in Chinese hamster ovary (CHO)-K1 cells expressing a human 5-HT1A receptor by 5-HT, prototypical 5-HT1A agonists, N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methyl-6-; methylaminopyridin-2-yl)-methylaminomethyl]-piperidine (F 14679), and especially N-(3-chloro-4-fluorobenzoyl)-4-fluoro-4-[(5-methylpyridin-2-yl)-; methylaminomethyl]piperidine (F 13640) as representative ligands of a new chemical class (methylamino-pyridine) that combines both high efficacy and selectivity for 5-HT1A receptors. 5-HT (pEC50 = 6.70 +/- 0.02) induced a pertussis toxin-sensitive, transient high-magnitude Ca2+ response. High-magnitude Ca2+ responses (Emax, percentage versus 5-HT) were also found with F 13640 (107 +/- 4), 5-carboxamidotryptamine (100 +/- 3), and F 14679 (87 +/- 3). In contrast, the prototypical 5-HT1A receptor agonists buspirone, ipsapirone, and 8-(hydroxy-2-(di-n-propylamino)tetralin, and also flesinoxan and eptapirone, were virtually inactive (< or =5). This atypical pattern of 5-HT1A receptor activation contrasts with the broad spectrum of the ligands' partial agonist properties as observed by measuring guanosine 5'-O-(3-[35 S]thio)triphosphate ([35S]GTPgammaS) binding responses with membranes of either CHO-K1 or C6-glial cells stably expressing a human 5-HT1A receptor. Remarkably, differences between ligands that seem small in the [35S]GTPgammaS binding assay translate into huge differences in the magnitude of Ca2+ responses. Therefore, some of these 5-HT1A ligands (i.e., F 13640) may in a selective way induce responses that may be not at all be achieved with other ligands (i.e., buspirone). In conclusion, the pharmacology of 5-HT1A receptor ligands seems to be codetermined by the effector pathway.
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PMID:Ca2+ responses in Chinese hamster ovary-K1 cells demonstrate an atypical pattern of ligand-induced 5-HT1A receptor activation. 1297 Mar 82

The effect of the novel imidazoline compound 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-(5-methyl-2,3-dihydrobenzofuran-7-yl)-ethyl]-pyridine (NNC77-0020) on stimulus-secretion coupling and hormone secretion was investigated in mouse pancreatic islets and isolated alpha- and beta-cells. In the presence of elevated glucose concentrations NNC77-0020 stimulated insulin secretion concentration dependently (EC(50) 64 nM) by 200% without affecting the whole-cell K(+) current or cytoplasmic Ca(2+) levels. Capacitance measurements in single mouse beta-cells showed that intracellular application of NNC77-0020 via the recording pipette enhanced Ca(2+)-dependent exocytosis. This action was dependent on protein kinase C (PKC) and cytoplasmic phospholipase A(2) (cPLA(2)) activity and required functional granular ClC-3 Cl(-) channels. In intact islets NNC77-0020 stimulated glucose-dependent somatostatin secretion, an effect that was also dependent on PKC and cPLA(2) activity. NNC77-0020 also inhibited glucagon secretion. In single mouse alpha-cells this action was not associated with a change in spontaneous electrical activity and resulted from a reduction in the rate of Ca(2+)-dependent exocytosis. Inhibition of exocytosis by NNC77-0020 was pertussis toxin sensitive and mediated by activation of the protein phosphatase calcineurin. In conclusion, our data suggest that the imidazoline compound NNC77-0020 modulates pancreatic hormone secretion in a complex fashion, comprising glucose-dependent stimulation of insulin and somatostatin secretion and inhibition of glucagon release. These mechanisms of action constitute an ideal basis for the development of novel imidazoline-containing anti-diabetic compounds.
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PMID:The imidazoline NNC77-0020 affects glucose-dependent insulin, glucagon and somatostatin secretion in mouse pancreatic islets. 1368 90

Lysophosphatidylserine (LPS) may be generated after phosphatidylserine-specific phospholipase A2 activation. However, the effects of LPS on cellular activities and the identities of its target molecules have not been fully elucidated. In this study, we observed that LPS stimulates an intracellular calcium increase in L2071 mouse fibroblast cells, and that this increase was inhibited by 1-[6-((17beta-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione (U-73122) but not by pertussis toxin, suggesting that LPS stimulates calcium signaling via G-protein coupled receptor-mediated phospholipase C activation. Moreover, LPS-induced calcium mobilization was not inhibited by the lysophosphatidic acid receptor antagonist, (S)-phosphoric acid mono-{2-octadec-9-enoylamino-3-[4-(pyridine-2-ylmethoxy)-phenyl]-propyl} ester (VPC 32183), thus indicating that LPS binds to a receptor other than lysophosphatidic acid receptors. It was also found that LPS stimulates two types of mitogen-activated protein kinase [i.e., extracellular signal-regulated protein kinase (ERK) and p38 kinase] in L2071 cells. Furthermore, these LPS-induced ERK and p38 kinase activations were inhibited by pertussis toxin, which suggests the role of pertussis toxin-sensitive G-proteins in the process. In terms of functional issues, LPS stimulated L2071 cell chemotactic migration, which was completely inhibited by pertussis toxin, indicating the involvement of pertussis toxin-sensitive G(i) protein(s). This chemotaxis of L2071 cells induced by LPS was also dramatically inhibited by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) and by 2'-amino-3'-methoxyflavone (PD98059). This study demonstrates that LPS stimulates at least two different signaling cascades, one of which involves a pertussis toxin-insensitive but phospholipase C-dependent intracellular calcium increase, and the other involves a pertussis toxin-sensitive chemotactic migration mediated by phosphoinositide 3-kinase and ERK.
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PMID:Lysophosphatidylserine stimulates L2071 mouse fibroblast chemotactic migration via a process involving pertussis toxin-sensitive trimeric G-proteins. 1636 94

Previous work has established the presence of functional P2X(7) subunits in rat cerebellar astrocytes, which after stimulation with 3'-O-(4-benzoyl)benzoyl ATP (BzATP) evoked morphological changes that were not reproduced by any other nucleotide. To further characterize the receptor(s) and signaling mechanisms involved in the action of BzATP, we have employed fura-2 microfluorometry and the patch-clamp technique. BzATP elicited intracellular calcium responses that typically exhibited two components: the first one was transient and metabotropic in nature--sensitive to phospholipase C inhibition and pertussis toxin treatment, whereas the second one was sustained and depended on the presence of extracellular calcium. The ionotropic nature of this latter component was corroborated by measurements of Mn(2+) entry and macroscopic non-selective cation currents evoked by either BzATP (100 muM) or ATP (1 mM). The two components of the calcium response to BzATP differed in their pharmacological sensitivity. The metabotropic component was partially sensitive to pyridoxalphosphate-5'-phosphate-6-azo-(-2-chloro-5-nitrophenyl)-2,4-disulfonate, a selective antagonist of P2Y(13) receptors, while the ionotropic component was modulated by external magnesium and markedly reduced by brilliant blue G and 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine (A438079), thus implying the involvement of P2X(7) purinergic receptors. It is concluded that P2Y(13) and P2X(7) purinergic receptors are functionally expressed in rat cerebellar astrocytes and mediate the increase in intracellular calcium elicited by BzATP in these cells.
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PMID:P2X7 and P2Y13 purinergic receptors mediate intracellular calcium responses to BzATP in rat cerebellar astrocytes. 1945 67


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