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)

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. 184 78

The prejunctional inhibitory effects of a series of 5-HT1 receptor agonists were examined against the isometric contraction of epididymal portions of rat vas deferens evoked by single stimulus pulses in the presence of nifedipine (10 mumol/l). The 5-HT1A ligand flesinoxan produced inhibition of contractions which was not inhibited by cyanopindolol or yohimbine. However, the prejunctional inhibitory concentration response curve for the 5-HT1 agonist 5-carboxamidotryptamine (5-CT) was biphasic in tissues from 1.5 month old animals but monophasic in tissues from 24 months animals. Cyanopindolol (1 mumol/l) antagonised the inhibitory effects of 5-CT in tissues from 1.5 and 3 month animals but not in tissues from 8 or 24 months animals. Inhibitory actions of 5-CT were not prevented by pretreating animals with pertussis toxin (6 micrograms/kg i.v.), a dose which abolished the negative inotropic response to acetylcholine in rat left atria. It is concluded that the nerve terminals of vas deferens from 1.5 month old animals contain both 5-HT1B and other as yet unclassified 5-HT1 receptors, but that this 5-HT1B-mediated response is lost in maturation and ageing.
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PMID:The effects of ageing on prejunctional 5-hydroxytryptamine receptors in the rat vas deferens. 223 97

Growth factors can be divided into two classes which act through distinct signal transduction pathways. One class including epidermal growth factor, platelet derived growth factor and fibroblast growth factor activates receptor tyrosine kinases, and the second class, including thrombin, bombesin, bradykinin and vasopressin activates a phosphoinositide-specific phospholipase C through GTP-binding proteins which can be inactivated by pertussis toxin. In Chinese hamster lung fibroblasts, thrombin-induced mitogenicity seems to correlate well with phospholipase C activation and both events are sensitive to pertussis toxin. Thrombin, like the other mitogens in this class, simultaneously inhibits adenylate cyclase. This involves an inhibitory G protein (Gi), a well established pertussis toxin substrate. The relative contributions of the two signalling pathways to mitogenicity has not been evaluated so far. We report here that the neurotransmitter serotonin (5-hydroxytryptamine), a contracting agent and mitogen for smooth muscle cells, activates phospholipase C, inhibits adenylate cyclase and stimulates DNA synthesis in fibroblasts. These events are sensitive to pertussis toxin. We show that the mitogenicity of 5-hydroxytryptamine can be uncoupled from phospholipase C activation that is mediated by 5-HT2 receptors, but correlates perfectly with inhibition of adenylate cyclase through 5-HT1B receptor. We propose that inhibition of adenylate cyclase or activation of an undefined effector system by Gi is important in 5-hydroxytryptamine induced DNA synthesis and contributes to the strong mitogenicity of the other members of this family of growth factors.
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PMID:Serotonin stimulates DNA synthesis in fibroblasts acting through 5-HT1B receptors coupled to a Gi-protein. 304 68

A clonal cell line derived from rat renal mesangial cells was shown to express endogenous 5-hydroxytryptamine (serotonin, 5-HT) receptors that mediate inhibition of cyclic AMP accumulation. These receptors were characterized as being of the 5-HT1B receptor subtype. 5-HT1 receptor agonists inhibited forskolin-stimulated cyclic AMP accumulation in rat renal mesangial cells (60-70% maximal inhibition) with the following rank order of potency (mean pEC50 values +/- SEM, n > or = 3): ergotamine (9.58 +/- 0.51) > RU 24969 (8.67 +/- 0.23) > or = 5-CT (8.42 +/- 0.06) > or = CP 93129 (8.15 +/- 0.27) > 5-HT (7.75 +/- 0.11) > sumatriptan (6.29 +/- 0.30) > 8-OH-DPAT (4.32 +/- 0.15). 5-HT2 and 5-HT4 receptor agonists were without effect. 5-HT-induced inhibition of cyclic AMP accumulation was abolished by a pre-treatment of the cells with pertussis toxin. (-)Propranolol was a partial agonist (27% maximal inhibition, pEC50 7.19 +/- 0.24, n = 3); when used as an antagonist at 1 microM, it shifted the concentration-response curve of 5-HT to the right (pKB 7.22 +/- 0.35, n = 3). Methiothepin was a competitive antagonist of 5-HT (pA2 8.04 +/- 0.10, Schild slope 0.87 +/- 0.21, n = 3). Rauwolscine (10 microM) had no antagonist activity. There was a significant correlation (r = 0.98, P = 0.0001) between the cyclic AMP data obtained in rat mesangial cells and 5-HT1B binding data reported in rat brain cortex. The same pattern of responses was observed in early passages of primary cultures of rat mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine 5-HT1B receptors inhibiting cyclic AMP accumulation in rat renal mesangial cells. 771 39

Analysis of the primary protein structure of the human serotonin1B (5-HT1B) receptor reveals consensus sites for phosphorylation and a putative site for palmitoylation. To investigate these posttranslational modifications, we have expressed a c-myc epitope-tagged 5-HT1B (m5-HT1B) receptor in Sf9 cells. This strategy enabled receptors to be detected by immunoblot analysis and purified by immunoprecipitation using a monoclonal antibody, 9E10, specific for the c-myc epitope. Agonist radioligand [3H]5-HT binding studies showed that the expressed 5-HT1B and m5-HT1B receptors displayed the characteristic pharmacological profile of the neuronal 5-HT1B receptor. The expressed receptors displayed both high- and low-affinity states for [3H]5-HT, suggesting that the receptors were coupled to endogenous G-proteins. Indeed, agonist binding to the high-affinity receptor state was regulated in the presence of GTP gamma S, Gpp(NH)p, and pertussis toxin. [32P]ADP-ribosylation experiments identified a major approximately 41-kDa ADP-ribosylated protein present in Sf9 membranes that comigrated with partially purified bovine brain Gi alpha/G(o) alpha subunits. Measurements of adenylyl cyclase activity in membranes from cells expressing m5-HT1B receptors showed that serotonergic agonists mediated the inhibition of adenylyl cyclase activity with a rank order of potency comparable to their affinity constants. Immunoblot analysis of membranes prepared from cells expressing m5-HT1B receptors and photoaffinity labeling of the immunoprecipitated material revealed photolabeled species at approximately 95 and at approximately 42 kDa.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Human serotonin1B receptor expression in Sf9 cells: phosphorylation, palmitoylation, and adenylyl cyclase inhibition. 821 42

5-Hydroxytryptamine 5-HT1B/5-HT1D receptors are members of the same receptor subfamily, but display a different pharmacology (Hartig et al. (1992) Trends Pharmacol Sci 13: 152-159). Whereas several cell lines have been reported to contain 5-HT1B receptors, none has been described, however, that endogenously expresses well-characterized 5-HT1D receptors. The present study deals with the identification of 5-HT1D receptors inhibiting cyclic AMP accumulation in Madin-Darby canine kidney (MDCK) cells. 5-HT (1 nM-10 microM) induced a concentration-dependent inhibition of the cyclic AMP accumulation stimulated by prostaglandin E1 (1 microM) in MDCK cells. The maximal effect of 5-HT averaged 50% inhibition and was abolished after a pre-treatment of the cells with pertussis toxin. Other agonists mimicked the effects of 5-HT, with the following rank order of potency (pEC50 +/- SEM, n > or = 3): 5-carboxamidotryptamine (8.36 +/- 0.48) > PAPP (p-aminophenylethyl-m-trifluoromethylphenyl piperazine. 7.89 +/- 0.23) > 5-HT (7.35 +/- 0.05) > sumatriptan (6.65 +/- 0.27). PAPP behaved as a partial agonist. 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) was less potent, its maximal effect being not reached at 0.1 mM. Methiothepin. GR127935, (-)propranolol, rauwolscine and ketanserin were all devoid of intrinsic activity (up to 10 microM or 0.1 mM). Methiothepin (10 nM. 0.1 microM and 1 microM) antagonized 5-HT effect (pA2 8.57 +/- 0.44. Schild slope 1.17 +/- 0.21, n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine 5-HT1D receptors mediating inhibition of cyclic AMP accumulation in Madin-Darby canine kidney (MDCK) cells. 858 40

Our study was undertaken to characterize the functional properties of 5-hydroxytryptamine (5-HT)1D receptors in the rat midbrain raphe nuclei. In a first series of experiments, designed to assess whether 5-HT1D receptors are coupled to Gi/o proteins, the intracerebral injection of pertussis toxin into the dorsal raphe as well as incubation of midbrain raphe slices with the alkylating agent N-ethyl-maleimide (NEM) reduced the efficacy of the 5-HT1B/1D agonist sumatriptan to inhibit the electrically evoked overflow of [3H]5-HT from preloaded slices. Furthermore, preincubation with NEM also reduced the efficacy with which the 5-HT1B/1D antagonist GR 127935 enhanced evoked overflow of [3H]5-HT. These results indicate that, in rat midbrain raphe nuclei, 5-HT1D receptors are linked to Gi/o proteins. In an attempt to determine whether 5-HT1D receptors are located on 5-HT neurons, the inhibitory effect of sumatriptan and of the nonselective 5-HT agonist 5-carboxyamidotryptamine on K(+)-evoked overflow of [3H]5-HT was assessed in the presence of the Na+ channel blocker tetrodotoxin. Neither the inhibitory effect of sumatriptan nor that of 5-carboxyamidotryptamine were reduced by the addition of tetrodotoxin to the superfusion medium, suggesting that these 5-HT1D receptors are located on 5-HT neurons and may be considered autoreceptors. In a third series of experiments, rats were treated for 21 days either with the selective 5-HT reuptake inhibitor paroxetine (10 mg/kg/day, s.c.) or the reversible type A monoamine oxidase inhibitor befloxatone (0.75 mg/kg/day, s.c.) and superfusion experiments were performed after a 48-hr washout period. 5-HT1D receptors, similarly to 5-HT1A autoreceptors, desensitize after long-term treatment with a selective 5-HT reuptake inhibitor or a reversible type A monoamine oxidase inhibitor because the efficacy of sumatriptan and of 8-OH-DPAT to inhibit the electrically evoked overflow of [3H]5-HT was reduced after the administration of either drug.
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PMID:Regulation of 5-hydroxytryptamine release from rat midbrain raphe nuclei by 5-hydroxytryptamine1D receptors: effect of tetrodotoxin, G protein inactivation and long-term antidepressant administration. 863 39

1. Chinese hamster ovary cells (CHO-K1) express an endogenous 5-hydroxytryptamine (5-HT)1B-like receptor that is negatively coupled to adenylyl cyclase through a pertussis toxin (PTX)-sensitive mechanism. Furthermore, the human adenosine A1 receptor when expressed in CHO-K1 cells (CHO-A1) has been shown to mobilize intracellular Ca2+ through a PTX-sensitive mechanism. Therefore the aim of this investigation was to determine whether the endogenous 5-HT1B-like receptor was able to stimulate increases in intracellular free [Ca2+] ([Ca2+]i) in CHO-A1 cells. 2. In agreement with previous studies using CHO cells, 5-hydroxytryptamine (5-HT) elicited a concentration-dependent inhibition of forskolin-stimulated [3H]-cyclic AMP production in CHO-A1 cells (p[EC50] = 7.73 +/- 0.13). 5-HT (1 microM) inhibited 47 +/- 5% of the [3H]-cyclic AMP accumulation induced by 3 microM forskolin. Forskolin stimulated [3H]-cyclic AMP accumulation was also inhibited by the 5-HT1 receptor agonists (p[EC50] values) 5-carboxyamidotryptamine (5-CT; 8.07 +/- 0.08), RU 24969 (8.12 +/- 0.33) and sumatriptan (5.80 +/- 0.31). 3. 5-HT elicited a concentration-dependent increase in [Ca2+]i in CHO-A1 cells (p[EC50] = 8.07 +/- 0.05). In the presence of 2 mM extracellular Ca2+, 5-HT (1 microM) increased [Ca2+]i from 174 +/- 17 nM to 376 +/- 22 nM. The 5-HT1 receptor agonists (p[EC50] values), 5-carboxyamidotryptamine (5-CT; 7.9 +/- 0.02), RU 24969 (8.1 +/- 0.07) and sumatriptan (5.9 +/- 0.11) all elicited concentration-dependent increases in [Ca2+]i. Similar maximal increases in [Ca2+]i were obtained with each agonist. The selective 5-HT1A receptor agonist, 8-OH-DPAT (10 microM) did not stimulate increases in [Ca2+]i. 5-HT (100 microM) and 5-CT (10 microM) did not stimulate a measurable increase in [3H]-inositol phosphate accumulation in CHO-A1 cells. 4. 5-HT (1 microM)-mediated increases in [Ca2+]i were insensitive to the 5-HT receptor antagonist, ritanserin (5-HT2; 100 nM), ketanserin (5-HT2; 100 nM), LY-278,584 (5-HT3; 1 microM) and WAY 100635 (5-HT1A; 1 microM). The response to 5-HT (100 nM) was antagonized by the non-selective 5-HT1 antagonist, methiothepin (pKb = 8.90 +/- 0.09) and the 5-HT1D antagonist GR 127935 (pKb = 10.44 +/- 0.06). 5. Pretreatment with PTX (200 ng ml-1 for 4 h) completely attenuated the Ca2+ response to 100 microM 5-HT. 6. In untransfected CHO-K1 cells, 5-HT (1 microM), RU 24969 (1 microM), and 5-CT (1 microM) elicited increases in [Ca2+]i similar to those observed in CHO-A1 cells. 7. These data demonstrate that in CHO-K1 cells the endogenously expressed 5-HT1B-like receptor couples to the phospholipase C/Ca2+ signalling pathway through a PTX-sensitive pathway, suggesting the involvement of Gi/Go protein(s).
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PMID:Coupling of an endogenous 5-HT1B-like receptor to increases in intracellular calcium through a pertussis toxin-sensitive mechanism in CHO-K1 cells. 868 Jul 21

The effect of Gi coupled receptor activation (adenosine A1 and 5-HT1B receptors) on cholecystokinin receptor-stimulated inositol phosphate accumulation has been investigated in Chinese hamster ovary cells transfected with the human adenosine A1 receptor cDNA (CHO-A1). CHO cells constitutively express the 5-HT1B receptor [Berg, Clarke, Sailstad, Saltzman and Maayani (1994) Mol. Pharmacol. 46, 477-484]. Our previous studies using CHO-A1 cells have revealed that both the adenosine A1 and 5-HT1B receptor are negatively coupled to adenylyl cyclase activity and stimulate increases in [Ca2+]i, through a pertussis toxin-sensitive pathway. In the present study the selective adenosine A1 receptor agonist N6-cyclopentyladenosine stimulated a pertussis toxin-sensitive increase in total [3H]inositol phosphate accumulation. The sulphated C-terminal octapeptide of cholecystokinin (CCK-8) stimulated a robust and pertussis toxin-insensitive increase in [3H]inositol phosphate accumulation through the activation of CCKA receptors. Co-stimulation of CHO-A1 cells with N6-cyclopentyladenosine and CCK-8 produced a synergistic increase in [3H]inositol phosphate accumulation. The synergistic interaction between N6-cyclopentyladenosine and CCK-8 was abolished in pertussis toxin-treated cells. Synergy between N6-cyclopentyladenosine and CCK-8 still occurred in the absence of extracellular calcium. The 5-HT1B receptor agonist 5-carboxyamidotryptamine did not stimulate a measurable increase in [3H]inositol phosphate accumulation. Furthermore, 5-carboxyamidotryptamine had no significant effect on CCK-8 mediated [3H]inositol phosphate production. Activation of endogenous P2U receptors (Gq/Gll coupled) with ATP gamma S produced a significant increase in [3H]inositol phosphate accumulation. Co-stimulation of CHO-A1 cells with ATP gamma S and CCK-8 produced additive increases in [3H]inositol phosphate accumulation. These data indicate that CHO-A1 cells may prove a useful model system in which to investigate further the mechanisms underlying the intracellular 'cross-talk' between phospholipase C coupled receptors (Gq/Gll linked) and Gi/Go coupled receptors.
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PMID:Synergistic interactions between human transfected adenosine A1 receptors and endogenous cholecystokinin receptors in CHO cells. 879 Oct 2

Serotonin acts on 5-hydroxytryptamine (5-HT)1B-like receptors in isolated rabbit ear artery precontracted with phenylephrine (PHE). These receptors are inactive, or "silent," in untreated vessels. Ear artery rings were mounted in tissue baths for the measurement of isometric contraction to further characterize these 5-HT1B-like receptors. The 5-HT1-selective receptor agonist sumatriptan failed to contract the untreated ear artery rings but caused a powerful, concentration-dependent contraction in PHE-precontracted vessels. The 5-HT1A/rat 1B receptor antagonist propranolol (1 microM) had no effect, whereas the 5-HT1B receptor antagonists rauwolscine (0.1 microM) and GR127935 (1-100 nM) markedly inhibited the contraction to sumatriptan. In vessels precontracted with phenylephrine, nifedipine reduced and calcium-free medium abolished the contractile response to serotonin. Relaxation to the adenylate cyclase activator forskolin was studied in contracted ear artery rings. Low concentrations (0.1-0.3 microM) of forskolin rapidly and completely relaxed ear artery rings contracted with PHE. In contrast, when PHE-precontracted vessels were contracted with either serotonin or sumatriptan, forskolin caused little or no relaxation at low concentrations and only partial relaxation at 10- to 30-fold higher concentrations. The resistance of these vessels to relaxation by forskolin was markedly reduced in the presence of GR127935 or in ear artery rings from pertussis toxin-treated rabbits. However, pertussis toxin treatment had no effect on the contractile response of PHE-precontracted ear artery rings to serotonin. It is concluded that the silent 5-HT1-like receptor of rabbit ear artery closely resembles the 5-HT1B receptor subtype. This receptor is inversely coupled to adenylate cyclase through a pertussis toxin-sensitive G protein; however, this coupling is unlikely to contribute to the serotonin-induced contraction of PHE-precontracted ear artery rings. Instead, this contraction is mediated at the second-messenger level by pertussis toxin-insensitive influx of calcium.
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PMID:Pharmacological characterization of the "silent" 5-hydroxytryptamine1B-like receptors of rabbit ear artery. 935 82


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