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 purpose of these studies was to determine how exposure to FSH affects subsequent responsiveness of adenylyl cyclase and progesterone production to FSH in immature porcine granulosa cells in vitro. Acute cAMP and progesterone responses to FSH and the postreceptor activators of cyclase, forskolin and cholera toxin, were determined after a 24-h preincubation with FSH. Pretreatment with FSH (1-1000 ng/ml) resulted in an increase in subsequent basal progesterone production which was dependent on preincubation FSH concentration. The cAMP response to FSH, on the other hand, was reduced after preincubation with FSH in a manner dependent on preincubation FSH concentration. Removal of FSH with acidified medium and subsequent incubation in FSH-free medium resulted in recovery of the cAMP response to FSH, indicating that attenuation of the response is reversible. Attenuation of the cAMP response to FSH does not appear to be due to 1) a loss of activity of the catalytic moiety of cyclase, since the response to forskolin and cholera toxin was not decreased by FSH; 2) a decrease in coupling of the stimulatory guanine nucleotide regulatory protein with the catalytic moiety of cyclase, since the response to cholera toxin was not reduced by FSH; 3) inhibitory signals, since preincubation with pertussis toxin did not affect the subsequent response to FSH; or 4) cAMP itself, since neither cholera toxin nor the cAMP analog 8-(4-chlorophenyl-thio)cAMP affected the response to FSH. It appears, instead, that FSH regulates FSH responsiveness by regulating the interaction of the FSH receptor with stimulatory guanine nucleotide regulatory protein.
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PMID:Autoregulation of acute progesterone and adenosine 3',5'-monophosphate responses to follicle-stimulating hormone (FSH) in porcine granulosa cells: effects of FSH, cholera toxin, forskolin, and pertussis toxin. 284 9

The antinociceptive effects of the putative endogenous cannabinoid ligand anandamide (ANA) and its fluorinated analog, fluoroanandamide (FA), were determined as measured by the tail-flick and p-phenylquinone (PPQ) stretch tests. The ED50 values (confidence limits) for ANA and FA were 77 (52-13) and 7 (2-21) micrograms/mouse, respectively, for the tail-flick test and 30 (23-41) and 0.5 (0.1-2) micrograms/mouse, respectively, for the PPQ test after intrathecal (i.t.) administration. ANA was not significantly less potent than delta 9-tetrahydrocannabinol (THC) in the tail-flick test, but it was less potent in the PPQ test. FA was more potent than either ANA or THC in tail-flick test. The antinociceptive effects of all drugs (administered i.t.) were blocked significantly or nearly abolished by the pretreatment of the mice with pertussis toxin (i.t.). Pretreatment of the mice with 5 and 25 micrograms forskolin per mouse or 10 micrograms 8-(4-chlorophenyl-thio)-adenosine-3',5'-monophosphate cyclic monosodium salt per mouse (both i.t.) significantly attenuated the antinociception produced by THC but not by ANA or FA. Various calcium modulators were tested in combination with THC, ANA, and FA, but they failed to alter the antinociceptive effects of the drugs. Various potassium channel blockers were tested in combination with the drugs. Apamin, a blocker of small (low)-conductance calcium-gated potassium channels that attenuates THC-induced antinociception, failed to alter ANA- or FA-induced antinociception. In contrast to THC, which is blocked by the kappa antagonist nor-binaltorphimine, ANA- and FA-induced antinociception was not altered by classic opioid antagonists. Also in contrast to THC, which enhances mu and delta opioid-induced antinociceptive effects, ANA failed to significantly alter opioid antinociception. ANA significantly shifted the THC dose-effect curve to the right. Thus, ED50 for DMSO/THC in the tail-flick test was shifted from 14 (7-29) to 54 (38-77) micrograms/mouse and was shifted in the hot-plate test from 22 (12-42) to 63 (43-92) micrograms/mouse. The magnitude of the shift in the ED50 was 3.8-fold in the tail-flick test and 2.9-fold in the hot-plate test. The shifts were parallel and significant. The Ki for the displacement of 3H-CP 55,940 binding by ANA and FA was 214 nM (+/- 45 S.E.M.) and 72 nM (+/- 5 S.E.M.), respectively, in pure spinal cord synaptosomes from the rat. ANA and FA were significantly cross-tolerant to THC. Although similarities between ANA and cannabinoids were shown, several marked differences were observed between ANA and the classic cannabinoids. ANA appears to function as both a cannabimimetic and a blocker of cannabinoid-induced antinociception.
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PMID:Characterization of anandamide- and fluoroanandamide-induced antinociception and cross-tolerance to delta 9-THC after intrathecal administration to mice: blockade of delta 9-THC-induced antinociception. 779 Oct 96

The purpose of this study was to investigate whether anandamide induces cannabimimetic responses, mainly mobilization of arachidonic acid, in primary cultures of rat brain cortical astrocytes. Confluent monolayer cultures of astrocytes, prelabeled with [3H]arachidonic acid, were incubated with anandamide or delta9-tetrahydrocannabinol (delta9-THC) in the presence or absence of thimerosal, a fatty acid acyl CoA transferase inhibitor and phenylmethylsulfonyl fluoride, an amidohydrolase inhibitor. Anandamide and delta9-THC induced a time- and concentration-dependent release of arachidonic acid in the presence, but not in the absence, of thimerosal. Anandamide- and delta9-THC-stimulated arachidonic acid release was pertussis toxin-sensitive, indicating a receptor/G-protein involvement. A novel and selective cannabinoid receptor antagonist, SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4- methyl-1H-pyrazole-3-carboximide hydrochloride], blocked the arachidonic acid release, suggesting a cannabinoid receptor-mediated pathway. In astrocytes, the magnitude of anandamide-induced arachidonic acid release was equal to that released by equimolar concentrations of delta9-THC. Furthermore, direct assay of amidohydrolase activity indicated that degradation of anandamide into arachidonic acid and ethanolamine was negligible in cortical astrocytes. Our results suggest that anandamide stimulates receptor-mediated release of arachidonic acid, and the receptor may be the cannabinoid receptor. Astrocytes, containing a cannabinoid receptor and lower or negligible amidohydrolase activity, may be an important brain cell model in which to study the cannabimimetic effects of anandamide at a cellular and molecular level.
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PMID:Anandamide- and delta9-tetrahydrocannabinol-evoked arachidonic acid mobilization and blockade by SR141716A [N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4 -methyl-1H-pyrazole-3-carboximide hydrochloride]. 861 4

Treatment of cells with LPS-free oxLDL significantly enhanced protein kinase C (PKC) activity in cell extracts from P388D1 macrophage-like cells as determined by phosphorylation of histone H1 or Ac-MBP[4-14] substrate peptide. This effect was abolished by the PKC inhibitors H-7 and bisindolylmaleimide I while pertussis toxin failed to block stimulation. The phosphotransferase activity was also increased by acetylated LDL (acLDL) and maleylated albumin (malBSA), the oxLDL effect was inhibited by chloroquine which also blocked oxLDL-induced stimulation of tyrosine kinase activity. Marginal stimulation of PKC activity was observed when lipid extracts from oxLDL were used, indicating that uptake via scavenger receptors (SR) is mandatory. Polyinosinic acid (poly I) exhibited a concentration-dependent inhibition of the oxLDL-induced effect suggesting that SR II/I but not CD36 interactions are critical to PKC activation. Modified (lipo)proteins increased the concentration of diacylglycerol and differentially affected the levels of individual PKC isoenzymes predominantly in the cytosolic fraction. Changes of activity induced by oxLDL could be primarily assigned to alterations of the activities and levels of the isoenzymes beta and delta. Treatment with oxLDL, acLDL, and malBSA was also accompanied by increased production of prostaglandins as well as by an enhanced level of cyclooxygenase 2 (COX 2) as determined by Western blot analysis. Effects (correction) of oxLDL on PKC activity/expression was suppressed by the cyclooxygenase, 2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,2-dihydro-1H-pyrrolizine-5- ylacetic acid (ML 3000), and by treatment with the specific COX 2-inhibitor N-(2-cyclohexyloxy-4-nitrophenyl) methane-sulfonamide (NS-398). These results indicate that oxLDL, acLDL, and malBSA exhibit a COX 2-dependent and isotype specific effect on PKC in P388D1 cells following uptake via SR II/I and subsequent lysosomal degradation.
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PMID:Oxidized low-density lipoprotein stimulates protein kinase C (PKC) and induces expression of PKC-isotypes via prostaglandin-H-synthase in P388D1 macrophage-like cells. 866 83

It has long been established that the cannabinoid CB1 receptor transduces signals through a pertussis toxin-sensitive Gi/Go inhibitory pathway. Although there have been reports that the cannabinoid CB1 receptor can also mediate an increase in cyclic AMP levels, in most cases the presence of an adenylyl cyclase costimulant or the use of very high amounts of agonist was necessary. Here, we present evidence for dual coupling of the cannabinoid CB receptor to the classical pathway and to a pertussis toxin-insensitive adenylyl cyclase stimulatory pathway initiated with low quantities of agonist in the absence of any costimulant. Treatment of Chinese hamster ovary (CHO) cells expressing the cannabinoid CB1 receptor with the cannabinoid CP 55,940, {(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl) cyclohexan-1-ol} resulted in cyclic AMP accumulation in a dose-response manner, an accumulation blocked by the cannabinoid CB1 receptor-specific antagonist SR 141716A, {N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride}. In CHO cells coexpressing the cannabinoid CB1 receptor and a cyclic AMP response element (CRE)-luciferase reporter gene system, CP 55,940 induced luciferase expression by a pathway blocked by the protein kinase A inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-89). Under the same conditions the peripheral cannabinoid CB2 receptor proved to be incapable of inducing cAMP accumulation or luciferase activity. This incapacity allowed us to study the luciferase activation mediated by CB /CB2 chimeric constructs, from which we determined that the first and second internal loop regions of the cannabinoid CB1 receptor were involved in transducing the pathway leading to luciferase gene expression.
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PMID:Dual intracellular signaling pathways mediated by the human cannabinoid CB1 receptor. 1042 89

The mitogen-activated protein kinase (MAPK) family consists of the p42/p44 MAPKs and the stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38 MAPK. We have previously reported that the human adenosine A(1) receptor stimulates p42/p44 MAPK in transfected Chinese hamster ovary cells. In this study, we have investigated whether the endogenous adenosine A(1) receptor in the smooth muscle cell line, DDT(1)MF-2 activates p42/p44 MAPK, JNK and p38 MAPK. The adenosine A(1) receptor agonist N(6)-cyclopentyladenosine stimulated time and concentration-dependent increases in p42/p44 MAPK and p38 MAPK phosphorylation in DDT(1)MF-2 cells. No increases in JNK phosphorylation were observed following adenosine A(1) receptor activation. N(6)-cyclopentyladenosine-mediated increases in p42/p44 MAPK and p38 MAPK phosphorylation were blocked by the selective adenosine A(1) receptor antagonist 1,3-dipropylcyclopentylxanthine and following pretreatment of cells with pertussis toxin. Furthermore, adenosine A(1) receptor-mediated increases in p42/p44 MAPK were sensitive to the MAPK kinase 1 inhibitor PD 98059 (2'-amino-3'-methoxyflavone), whereas p38 MAPK responses were blocked by the p38 MAPK inhibitor SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole). The broad range protein tyrosine kinase inhibitors genistein and tyrphostin A47 (alpha-cyano-(3,4-dihydroxy)thiocinnamide) did not block adenosine A(1) receptor stimulation of p42/p44 MAPK. For comparison, insulin-mediated increases in p42/p44 MAPK were blocked by genistein and tyrphostin A47. The Src tyrosine kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) and the epidermal growth factor receptor tyrosine kinase inhibitor AG1478 (4-(3-chloroanilino)-6,7-dimethoxyquinazoline) also had no effect on adenosine A(1) receptor stimulation of p42/p44 MAPK. Furthermore, the protein kinase C inhibitors Ro 31-8220 (3-[1-[3-(2-isothioureido) propyl]indol-3-yl]-4-(1-methylindol-3-yl)-3-pyrrolin-2,5-dione), chelerythrine and GF 109203X (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)-maleimide) were without effect on adenosine A(1) receptor-induced p42/p44 MAPK phosphorylation. In contrast, wortmannin and LY 294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one), inhibitors of phosphatidylinositol 3-kinase, attenuated adenosine A(1) receptor stimulation of p42/p44 MAPK phosphorylation. In conclusion, the adenosine A(1) receptor stimulates p42/p44 MAPK through a pathway which appears to be independent of tyrosine kinase activation but involves phosphatidylinositol 3-kinase. Finally, adenosine A(1) receptor stimulation in DDT(1)MF-2 cells also activated p38 MAPK but not JNK via a pertussis toxin-sensitive pathway.
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PMID:Regulation of p42/p44 MAPK and p38 MAPK by the adenosine A(1) receptor in DDT(1)MF-2 cells. 1122 88

We studied the delay in gastric emptying and gastrointestinal transit induced by the cannabinoid receptor agonists (+)-WIN 55,212-2 (R(+)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate) and CP 55,940 ((-)-cis-3[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol), as prevented by the selective cannabinoid CB(1)-receptor antagonist SR141716 ((N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide)) in rats after systemic or central drug administration. Oral SR141716 showed comparable potency (ID(50) range 1.0-3.9 mg/kg) in antagonizing gastric emptying and gastrointestinal transit delay by (+)-WIN 55,212-2 or CP 55,940. Gastric emptying and gastrointestinal transit delay after intracerebroventricular (i.c.v.) (+)-WIN 55,212-2 was prevented by oral or i.c.v. SR141716, but i.c.v. SR141716 did not significantly reduce the effect of i.p. (+)-WIN 55,212-2. Pertussis toxin prevented the delaying action of i.c.v. (+)-WIN 55,212-2 on both gastric emptying and gastrointestinal transit, but had no effect on (+)-WIN 55,212-2 i.p. These findings are consistent with a primary role of peripheral cannabinoid CB(1) receptor mechanisms in gastrointestinal transit delay by specific agonists.
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PMID:Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors. 1217 12

Stimulation of the beta(2)-adrenergic receptor (beta(2)AR) in human embryonic kidney (HEK) 293 cells causes a transient activation of Extracellular Signal-Regulated Kinase (ERK) 1/2. One of the mechanisms proposed for this activation is a PKA-mediated phosphorylation of the beta(2)AR that switches receptor coupling from G(s) to G(i) and triggers internalization of the receptor. To examine these phenomena, we characterized agonist activation of ERK1/2 in HEK293 cells by the endogenous beta(2)AR and in HEK293 cells stably overexpressing either the wild-type beta(2)AR or a substitution mutant beta(2)AR (PKA(-)) that lacks the cyclic AMP-dependent protein kinase (PKA) consensus phosphorylation sites (S261A, S262A and S345A, S346A). As the baseline, we established that epinephrine stimulation of the endogenous beta(2)AR in HEK293 cells (20-30 fmol/mg) caused a rapid and transient activation of ERK1/2 with an EC(50) of 5 to 6 nM. In contrast, the potency of epinephrine stimulation of ERK1/2 in cells stably overexpressing WTbeta(2)AR and PKA(-) (2-4 pmol of beta(2)AR/mg) was increased by over 100-fold relative to HEK293 cells, the EC(50) values being 20 to 60 pM. The nearly identical 100-fold shift in EC(50) for ERK1/2 activation in the PKA(-) and WTbeta(2)AR relative to that in the HEK293 showed that the PKA(-) are fully capable of activating ERK1/2. We also found maximal activation of ERK1/2 in the overexpressing cell lines at concentrations of epinephrine that cause no internalization (i.e., the EC(50) for internalization was 75 nM). Pertussis toxin pretreatment caused only a weak inhibition of epinephrine activation of ERK1/2 in the HEK293 (7-16%) and no inhibition in the PKA(-) cells. Finally we found that the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (10 microM) caused a >90% inhibition of epinephrine or forskolin activation of ERK1/2 in both cell lines. Our results indicate that the dominant mechanism of beta(2)AR activation of ERK1/2 does not require PKA phosphorylation of the beta(2)AR, receptor internalization or switching from activation of G(s) to G(i) but clearly requires activation of a Src family member that may be downstream of PKA.
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PMID:Beta(2)-adrenergic receptor lacking the cyclic AMP-dependent protein kinase consensus sites fully activates extracellular signal-regulated kinase 1/2 in human embryonic kidney 293 cells: lack of evidence for G(s)/G(i) switching. 1239 Dec 72

In the present study, we observed evidence of cross-talk between the cannabinoid receptor CB1 and the orexin 1 receptor (OX1R) using a heterologous system. When the two receptors are co-expressed, we observed a major CB1-dependent enhancement of the orexin A potency to activate the mitogen-activated protein kinase pathway; dose-responses curves indicated a 100-fold increase in the potency of orexin-mediated mitogen-activated protein kinase activation. This effect required a functional CB1 receptor as evidenced by the blockade of the orexin response by the specific CB1 antagonist, N-(piperidino-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (SR141716), but also by pertussis toxin, suggesting that this potentiation is Gi-mediated. In contrast to OX1R, the potency of direct activation of CB1 was not affected by co-expression with OX1R. In addition, electron microscopy experiments revealed that CB1 and OX1R are closely apposed at the plasma membrane level; they are close enough to form hetero-oligomers. Altogether, for the first time our data provide evidence that CB1 is able to potentiate an orexigenic receptor. Considering the antiobesity effect of SR141716, these results open new avenues to understand the mechanism by which the molecule may prevent weight gain through functional interaction between CB1 and other receptors involved in the control of appetite.
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PMID:Hypersensitization of the Orexin 1 receptor by the CB1 receptor: evidence for cross-talk blocked by the specific CB1 antagonist, SR141716. 1269 Jan 15

The effect of the endogenous cannabinoid ligand anandamide on the function of the cloned alpha7 subunit of the nicotinic acetylcholine (ACh) receptor expressed in Xenopus oocytes was investigated by using the two-electrode voltage-clamp technique. Anandamide reversibly inhibited nicotine (10 microM) induced-currents in a concentration-dependent manner (10 nM to 30 microM), with an IC50 value of 229.7 +/- 20.4 nM. The effect of anandamide was neither dependent on the membrane potential nor meditated by endogenous Ca2+ dependent Cl- channels since it was unaffected by intracellularly injected BAPTA and perfusion with Ca2+-free bathing solution containing 2 mM Ba2+. Anandamide decreased the maximal nicotine-induced responses without significantly affecting its potency, indicating that it acts as a noncompetitive antagonist on nicotinic acetylcholine (nACh) alpha7 receptors. This effect was not mediated by CB1 or CB2 receptors, as neither the selective CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR 141716A) nor CB2 receptor antagonist N-((1S)-endo-1,3,3-trimethyl-bicyclo-heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR 144528) reduced the inhibition by anandamide. In addition, inhibition of nicotinic responses by anandamide was not sensitive to either pertussis toxin treatment or to the membrane permeable cAMP analog 8-Br-cAMP (0.2 mM). Inhibitors of enzymes involved in anandamide metabolism including phenylmethylsulfonyl fluoride, superoxide dismutase, and indomethacin, or the anandamide transport inhibitor AM404 did not prevent anandamide inhibition of nicotinic responses, suggesting that anandamide itself acted on nicotinic receptors. In conclusion, these results demonstrate that the endogenous cannabinoid anandamide inhibits the function of nACh alpha7 receptors expressed in Xenopus oocytes in a cannabinoid receptor-independent and noncompetitive manner.
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PMID:The endogenous cannabinoid anandamide inhibits alpha7 nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes. 1276 52


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