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)

The effects of chronic caffeine on the A1 adenosine receptor-adenylate cyclase system of rat cerebral cortical membranes were studied. Caffeine treatment significantly increased the number of A1 adenosine receptors as determined with the A1 adenosine receptor antagonist radioligand [3H]xanthine amine congener (XAC). R-PIA (agonist) competition curves constructed with [3H]XAC were most appropriately described by a two affinity state model in control membranes with a KH of 2.1 +/- 0.8 and a KL of 404 +/- 330 nM with 50 +/- 4% of receptors in the high affinity state (%RH). In contrast, in membranes from treated animals, there was a marked shift towards the high affinity state. In three of seven animals all of the receptors were shifted to a unique high affinity state which was indistinguishable from the KH observed in membranes from control animals. In four of seven animals the %RH increased from 50 to 69% with KH and KL indistinguishable from the control values. Thus, the agonist specific high affinity form of the receptor was enhanced following caffeine treatment. Maximal inhibition of adenylate cyclase activity in cerebral cortical membranes by R-PIA (1 microM) was significantly increased by 28% following caffeine treatment, consistent with an increased coupling of receptor-Gi protein with adenylate cyclase. Importantly, the quantity of Gi (alpha i) in rat cerebral cortex, determined by pertussis toxin-mediated labeling, was also increased to 133% of control values by this treatment. Thus, multiple components and interactions of the A1 adenosine receptor-adenylate cyclase complex are regulated by caffeine. These changes are likely compensatory measures to offset blockade of A1 receptors in vivo by caffeine and lead to a sensitization of this inhibitory receptor system.
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PMID:Multiple components of the A1 adenosine receptor-adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion. 339 8

Adenosine, via interaction with A1 adenosine receptors, increases insulin sensitivity and inhibits lipolysis in adipocytes. To investigate regulation of this system, adipocytes were incubated for up to 72 h with the nonmetabolizable adenosine receptor agonist, N6-phenylisopropyl adenosine (PIA). Adenosine receptors were measured by the binding of 125I-hydroxyphenylisopropyl adenosine to membranes. PIA down-regulated adenosine receptors, decreasing the number of binding sites with no change in affinity. Adipocytes were incubated for 48 h without or with 100 nM PIA to down-regulate the A1 receptors by approximately 60%. The cells were washed, and lipolysis and glucose transport were assessed. The ability of PIA to inhibit lipolysis was markedly attenuated in the down-regulated cells. Furthermore, the EC50 of insulin was increased approximately 3-fold in the PIA-treated cells. 125I-Insulin binding to the PIA-treated cells was unchanged, demonstrating that the decreased insulin sensitivity is not due to decreased insulin receptor binding. Pertussis toxin catalyzed ADP-ribosylation of a 41-kDa protein thought to be the alpha-subunit of Gi. This 41-kDa protein was decreased in membranes from cells treated with PIA, with a maximal 50% loss. This suggests that Gi is down-regulated and that loss of both the A1 adenosine receptor and Gi are involved in the metabolic changes observed after PIA treatment.
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PMID:Adenosine receptor down-regulation and insulin resistance following prolonged incubation of adipocytes with an A1 adenosine receptor agonist. 368 Feb 21

Adenosine, acting via A1 adenosine receptors, can inhibit adenylate cyclase activity in adipocytes. To assess the effects of chronic adenosine agonist exposure on the A1 adenosine receptor system of adipocytes, rats were infused with (-)-phenylisopropyladenosine or vehicle for 6 days and membranes were prepared. Basal as well as isoproterenol-, sodium fluoride-, and forskolin-stimulated adenylate cyclase activities were significantly increased (approximately 2-fold) in membranes from treated animals. (-)-Phenylisopropyladenosine-mediated inhibition of forskolin-stimulated adenylate cyclase activity was significantly (p = 0.0001) attenuated in membranes from treated rats (20.1 +/- 2.1% inhibition) versus controls (31.6 +/- 2.3% inhibition). Prostaglandin E1-induced inhibition of forskolin-stimulated adenylate cyclase activity was also attenuated: 11.7 +/- 3.6 versus 23.2 +/- 4.6% (p = 0.001). Using the A1 adenosine receptor agonist radioligand (-)-N6-(3-[125I]iodo-4-hydroxyphenylisopropyl)adenosine, 32% fewer high affinity binding sites were detected in membranes from treated animals (p less than 0.04). Photoaffinity labeling with N6-2-(3-[125I]iodo-4-azidophenyl)ethyladenosine revealed no gross difference in receptor structure. The number of beta-adrenergic receptors as well as the percentage of receptors in the high affinity state as assessed by (-)-3-[125I]iodocyanopindolol binding were the same in both groups. In membranes from treated rats, the amount of [alpha-32P]NAD incorporated by pertussis toxin into the alpha subunit of the inhibitory guanine nucleotide regulatory protein (Ni) was decreased by 37 +/- 11%. Concurrently, the quantity of label incorporated by cholera toxin into the alpha subunit of the stimulatory guanine nucleotide regulatory protein (Ns) was increased by 44 +/- 14% in treated membranes. Finally, the capacity of Ns solubilized from treated membranes to stimulate adenylate cyclase activity when reconstituted into cyc- S49 lymphoma cell membranes was enhanced by approximately 50% compared to control. Thus, heterologous desensitization, manifested by a diminished capacity to inhibit adenylate cyclase and an enhanced responsiveness to stimulatory effectors, can be induced in the A1 adenosine receptor-adenylate cyclase system of adipocytes. A decrease in Ni alpha subunit concomitant with an increase in Ns alpha subunit quantity and activity may represent the biochemical mechanism of desensitization in this system.
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PMID:Heterologous desensitization of the inhibitory A1 adenosine receptor-adenylate cyclase system in rat adipocytes. Regulation of both Ns and Ni. 380 10

Several reports from our laboratory have suggested the involvement of the brain adenosinergic system in ethanol-induced motor incoordination (EIMI). This study is an extension of the previous work and pertains to the evaluation of the role of the striatal adenosine in EIMI in male Sprague-Dawley rats. Using the motor incoordination induced by 1.5 g/kg of ethanol (ip) as a test response, the possible behavioral interactions between ethanol and adenosine agonists and antagonists in the striatum were investigated. Intrastriatal (IST) administration of adenosine A1-, A1 = A2-, and As-selective agonists, R(-)N6-(2-phenylisopropyl)adenosine (R-PIA), 5'-N-ethylcarboxamido-adenosine (NECA), and 5'-(N-cyclopropyl)-carboxamidoadenosine, respectively, significantly and dose-dependently accentuated EIMI when evaluated by rotorod test, suggesting the striatal adenosinergic modulation of EIMI. No significant change in normal motor coordination was noted, even when the highest IST doses of adenosine agonists were followed by saline instead of ethanol, suggesting that the observed behavioral interactions of these drugs were selective to ethanol. Hippocampus, which is known not to be involved in the normal motor functions, was selected as a control brain area because of the presence of high density of adenosine receptors, as well as the high levels of adenosine. Intrahippocampal NECA failed to alter EIMI, indicating the specific role of striatal and not hippocampal adenosinergic system in the modulation of EIMI. The potentiating effects of adenosine agonists N6-cyclohexyladenosine (CHA) and CGS-21680 on EIMI were blocked by adenosine A1- and A2-selective antagonists, 8-cyclopentyl-1,3-dipropylxanthine and 3,7-dimethyl-1-propargylxanthine, respectively, suggesting the participation of specific adenosine receptors in this functional interaction. A role for the adenosine A1 receptor in the striatal adenosinergic modulation of EIMI was favored based on the rank-order potency of adenosine agonists. IST pretreatment with pertussis toxin (PT), but not with PT beta-oligomer, nearly completely eliminated the accentuation of EIMI by CHA, further supporting the favored role of adenosine A1 receptors in EIMI. Histological and IST [3H]R-PIA distribution data confirmed that the observed behavioral effects were caused by exclusive striatal distribution of intrastriatally microinjected drugs. Data obtained suggested modulation of acute EIMI by striatal adenosine receptor-mediated mechanism(s) and the coupling of these adenosine receptor to the PT-sensitive Gi protein.
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PMID:Possible role of striatal adenosine in the modulation of acute ethanol-induced motor incoordination in rats. 748 36

Biochemical and pharmacological studies have established that adenosine modulates protein kinase C (PKC), which plays an important role in the maintenance of vascular tone. Our earlier studies [Marala and Mustafa. Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H271-H277, 1995. Marala, R. B., K. Ways, and S. J. Mustafa. Am. J. Physiol. 264 (Heart Circ. Physiol. 33): H1465-H1471, 1993] have shown the involvement of adenosine A1 receptors and not the A2 receptors in the upregulation of PKC in porcine coronary artery. The mechanism(s) by which adenosine upregulates PKC is not yet clearly understood. We now report the increased expression of PKC by adenosine A1 receptor through an upstream activation of pertussis toxin-sensitive G protein(s). Incubation of porcine coronary artery for 24 h with a relatively specific A1-receptor agonist (2S)-N6-(2-endo-norbornyl)adenosine (ENBA) elevated the contractile responses to endothelin-1 by about twofold, probably due to an increased expression of PKC. Incubation of porcine coronary artery with ENBA also protected against the phorbol 12,13-dibutyrate (PDBu)-induced depletion of PKC. Inclusion of pertussis toxin in the incubation medium completely blocked both the upregulatory and the protective effects of ENBA. Incubation with pertussis toxin did not alter the PKC activity as judged by the contractile responses to PDBu. On the contrary, incubation of porcine coronary artery with cholera toxin for 24 h did not alter any of the ENBA responses (upregulation of PKC and the protection against PDBu-induced PKC depletion). Incubation conditions of coronary arteries with toxins are sufficient to cause ADP ribosylation of respective G proteins as judged by back ADP ribosylation studies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine A1 receptor-induced upregulation of protein kinase C: role of pertussis toxin-sensitive G protein(s). 750 57

Release of substance P-like immunoreactivity (SP-LI) from dissociated enteric ganglia and the receptor-mediated prejunctional inhibition of this release were investigated with the use of a perifusion technique. SP-LI release was evoked by elevated extracellular K+ concentration and was inhibited, in a graded manner, by N6-cyclopentyl adenosine (CPA), an adenosine analogue with selectivity for adenosine A1 receptors. Similar inhibition of SP-LI release was obtained with 5-hydroxytryptamine (5-HT); incrementing concentrations, however, yielded a biphasic concentration-response relationship. The selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentyl-xanthine abolished the inhibition due to CPA, whereas the inhibitory action of 5-HT was sensitive to the 5-HT1A-selective antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide. Inhibition due to both agonists was insensitive to blockade by tetrodotoxin, suggesting a prejunctional locus for both adenosine and 5-HT1A receptors on the tachykininergic nerve endings. Pretreatment of ganglia with pertussis toxin had no effect on CPA-mediated inhibition of SP-LI release, whereas 5-HT-mediated inhibition was abolished. The findings demonstrate that adenosine and 5-HT receptors on enteric nerve endings are coupled to inhibition of tachykinin release through distinct mechanisms, putatively distinct G proteins.
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PMID:Adenosine and 5-HT inhibit substance P release from nerve endings in myenteric ganglia by distinct mechanisms. 768 28

COS-7 cells were transiently transfected with human thyrotropin receptor (TSHR) and dog A1 adenosine receptor (A1R) cDNA. TSH stimulated both inositol phosphate production and cyclic AMP (cAMP) accumulation in the cells. An A1 agonist, N6-(L-2-phenylisopropyl)adenosine (PIA), which is ineffective alone, significantly enhanced TSH-induced inositol phosphate production, but insignificantly inhibited TSH-induced cAMP accumulation was revealed by short-term treatment with the protein kinase C inhibitors, staurosporine and K252a, or long-term treatment with 12-myristate 13-acetate, suggesting that endogenous protein kinase C inhibits the A1R-mediated inhibition of the TSHR-adenylate cyclase system. In staurosporine-treated cells, the stimulatory and inhibitory permissive actions of PIA on TSH-induced phospholipase C and adenylate cyclase activation respectively were completely reversed by pretreatment with pertussis toxin whereas intrinsic TSH-induced effects were hardly affected by the toxin. The cross-talk between the signalling pathway for TSHR and that for A1R was not detected in a mixture of cells expressing either TSHR or A1R. We conclude that a single species of A1R, via pertussis-toxin-sensitive GTP-binding proteins, not only inhibits adenylate cyclase but also stimulates phospholipase C in collaboration with an activated TSHR within a single cell expressing both types of receptor.
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PMID:Intracellular cross-talk between thyrotropin receptor and A1 adenosine receptor in regulation of phospholipase C and adenylate cyclase in COS-7 cells transfected with their receptor genes. 770 64

The present study was conducted to test the hypothesis that adenosine attenuates the Ca2+ paradox (PD) injury via stimulation of adenosine A1 receptors linked to Gi proteins in the isolated rat heart. Treatment of adenosine reduced maximum lactate dehydrogenase release and ATP loss compared with regular Ca2+ PD. Recovery of mechanical activity after Ca2+ repletion was observed only in heart treated with adenosine before and during the Ca2+ PD. Significant preservation of myocytes was observed in adenosine-treated hearts compared with the regular Ca2+ PD. Adenosine exerted its effects in a dose-dependent manner, being maximum at 100 microM. The protective effects were mediated by adenosine A1 receptor activation since the adenosine A1 receptor agonist N6-phenylisopropyladenosine provided protection similar to adenosine-treated heart and was blocked by A1 receptor antagonist and pertussis toxin. This study suggests that protection by adenosine against the lethal injury of the Ca2+ PD is mediated by adenosine A1 receptor and a pertussis toxin-sensitive inhibiting G protein.
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PMID:Adenosine attenuates calcium paradox injury: role of adenosine A1 receptor. 773 32

Since adenosine A1 receptors activate phospholipase C (PLC) in DDT1 MF-2 smooth muscle cells we have examined whether phospholipase D (PLD) and protein kinase C (PKC) activities are also increased. The formation of diacylglycerol was also measured. PKC activity was determined by measuring the phosphorylation of two peptide substrates after rapidly permeabilizing the cells. PLD activity was determined by measuring the formation of phosphatidylethanol. N6-cyclopentyladenosine, a selective adenosine A1 receptor agonist (100 nM) and bradykinin (1 microM) both stimulated the formation of diacylglycerol. The activation was biphasic with a rapid, transient increase (within 1 min) followed by a second increase. N6-cyclopentyladenosine increased the activity of PKC (EC50 5.6 nM) and PLD (EC50 18.7 nM). This was blocked by treatment of cells with pertussis toxin or the adenosine A1 receptor selective antagonist, 8-cyclopentyl-1,3-dipropylxanthine. Ki values (3 nM for PKC; 0.1 nM for PLD) were consistent with responses mediated via adenosine A1 receptors. Bradykinin (1 microM) also increased PKC and PLD activity, but these responses were insensitive to pertussis toxin treatment. The activation of PKC by N6-cyclopentyladenosine or bradykinin was transient, reaching a maximum at 1-2 min, and was preceded by increases in the formation of diacylglycerol. When adenosine A1 and bradykinin receptors were activated simultaneously, a synergistic activation of PKC was seen. There was no synergistic effect on PLD activity. In summary, the present study shows that activation of adenosine receptors of the A1 subtype increases PKC and PLD activity. Simultaneous activation of adenosine A1 and bradykinin receptors causes a synergistic increase in PKC.
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PMID:Activation of adenosine A1 and bradykinin receptors increases protein kinase C and phospholipase D activity in smooth muscle cells. 777 Jan

Adenosine A1 receptors directly stimulate inositol phospholipid hydrolysis and Ca2+ mobilization through a pertussis toxin sensitive mechanism in DDT1MF-2 cells. In the present study we have investigated whether G protein beta gamma subunits (G beta gamma) are capable of stimulating phospholipase C in DDT1MF-2 cell membrane preparations using lipid vesicles containing [3H]phosphatidylinositol 4,5-bisphosphate. DDT1MF-2 cell membrane and soluble fractions were found to contain phospholipase C activity which was stimulated by increases in free Ca2+ ion concentration. G beta gamma purified from bovine retinal transducin produced significant increases in phospholipase C activity in DDT1MF-2 cell membranes. G beta gamma-dependent activation of phospholipase C, while virtually absent in the presence of low Ca2+ ion concentrations, increased markedly with increasing free Ca2+ ion concentration. These data suggest that membrane bound phospholipase C in DDT1MF-2 cells is sensitive to Ca2+, and may be stimulated conditionally by G beta gamma subunits, i.e. G beta gamma subunits activate the enzyme only in the presence of Ca2+. G beta gamma subunits also stimulated soluble phospholipase C in DDT1MF-2 cells. These findings support the hypothesis that Gi beta gamma subunits are involved in adenosine A1 receptor stimulated phospholipase C/Ca2+ signaling in DDT1MF-2 cells.
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PMID:Activation of phospholipase C by G-protein beta gamma subunits in DDT1MF-2 cells. 777 86


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