Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the regulation by adenosine of a 305-pS chloride (Cl-) channel in the apical membrane of a continuous cell line derived from rabbit cortical collecting duct (RCCT-28A) using the patch clamp technique. Stimulation of A1 adenosine receptors by N6-cyclohexyladenosine (CHA) activated the channel in cell-attached patches. Phorbol 12,13-didecanoate and 1-oleoyl 2-acetylglycerol, activators of protein kinase C (PKC), mimicked the effect of CHA, whereas the PKC inhibitor H7 blocked the action of CHA. Stimulation of A1 adenosine receptors also increased the production of diacylglycerol, an activator of PKC. Exogenous PKC added to the cytoplasmic face of inside-out patches also stimulated the Cl- channel. Alkaline phosphatase reversed PKC activation. These results show that stimulation of A1 adenosine receptors activates a 305-pS Cl-channel in the apical membrane by a phosphorylation-dependent pathway involving PKC. In previous studies, we showed that the protein G alpha i-3 activated the 305-pS Cl- channel (Schwiebert et al. 1990. J. Biol. Chem. 265:7725-7728). We, therefore, tested the hypothesis that PKC activates the channel by a G protein-dependent pathway. In inside-out patches, pertussis toxin blocked PKC activation of the channel. In contrast, H7 did not prevent G protein activation of the channel. We conclude that adenosine activates a 305-pS Cl- channel in the apical membrane of RCCT-28A cells by a membrane-delimited pathway involving an A1 adenosine receptor, phospholipase C, diacylglycerol, PKC, and a G protein. Because we have shown, in previous studies, that this Cl- channel participates in the regulatory volume decrease subsequent to cell swelling, adenosine release during ischemic cell swelling may activate the Cl-channel and restore cell volume.
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PMID:Adenosine regulates a chloride channel via protein kinase C and a G protein in a rabbit cortical collecting duct cell line. 131 18

We have studied the effect of stimulating protein kinase C with phorbol esters on the release of [3H]-noradrenaline (NA) in the absence or presence of presynaptic alpha 2-adrenoceptor blocking agents and compared that to the elevation of cyclic AMP levels more than 10-fold by a combination of rolipram and forskolin. 4-beta-Phorbol 12,13-dibutyrate (PDiBu) increased stimulated (3 Hz) [3H]-NA release markedly and in a concentration dependent manner. 4-alpha-Phorbol-12,13-didecanoate was ineffective. The effect of PDiBu was not significantly reduced by nifedipine (1 microM), but was proportionally less in the presence of an alpha 2-adrenoceptor antagonist, yohimbine. PDiBu inhibited the presynaptic effect of alpha 2-adrenoceptor agonists clonidine and UK 14304. By contrast, the presynaptic effect of the adenosine analogue R-PIA was not reduced by PDiBu. PDiBu caused an increase in cyclic AMP that depended on adenosine receptor stimulation. Elevation of cyclic AMP had a limited effect on NA release from rat hippocampus, and did not significantly decrease the presynaptic inhibitory effect of UK 14304 (0.1 microM), of morphine (1 microM) or of the adenosine A1-receptor agonist CHA (1 microM). The effect of phorbol esters and several presynaptic inhibitors of NA-release in the rat hippocampus cannot be explained by changes in cyclic AMP levels in the tissue. Phorbol esters that stimulate protein kinase C appear to interact with a target that is the site of action alpha 2-adrenoceptors in this tissue. This site is not a dihydropyridine sensitive Ca-channel and is also different from the target of presynaptic adenosine receptors. Thus, activation of protein kinase C discriminates between apparently similar presynaptic mechanisms.
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PMID:Protein kinase C activation increases noradrenaline release from the rat hippocampus and modifies the inhibitory effect of alpha 2-adrenoceptor and adenosine A1-receptor agonists. 284 95

To study the control of histamine release, we developed techniques for culturing fundic mucosal mast cells. After enzyme dispersion, enrichment by elutriation, and overnight suspension culture, mast cells accounted for 30% of the cells present. Histamine release into the medium, measured by radioenzymatic assay, was stimulated by the lectin concanavalin A (Con A). Ragweed antigen released histamine in antisera-sensitized cultures. Con A-induced histamine release was enhanced by adenosine, but adenosine alone was inactive. The relative potency of adenosine analogues was consistent with interaction at an adenosine A1-receptor site. The calcium ionophore A23187 (0.1-1 microM) also induced histamine release. Phorbol esters that activate protein kinase C, such as phorbol 12-myristate 13-acetate, did not release histamine but enhanced release when added to low concentrations of A23187. In contrast, inactive phorbols, such as 4 alpha-phorbol 12,13-didecanoate, failed to enhance A23187-induced release. Parallel studies with canine hepatic mast cells yielded comparable results. We conclude that canine fundic mast cells possess receptors for immunoglobulin E and adenosine. Our data are consistent with increases in cytosolic calcium and protein kinase C activation working synergistically to stimulate fundic mast cells.
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PMID:Modulation of histamine release from canine fundic mucosal mast cells. 296 15

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

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A1 receptor enhances the K+ and Cl- conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca2+ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A1 receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca2+ channels. The A1 and A2 receptors, coupled to Gi/G(o) and Gs proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A1 receptor may mimic metabotropic receptor stimulation in activating intracellular Ca2+ mobilization and PKC. A2 receptor mediated cAMP formation is depressed by high intracellular Ca2+ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A1 and A2 receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.
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PMID:Modulation of nerve and glial function by adenosine--role in the development of ischemic damage. 753 56

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A1 receptor stimulation which results in an upregulation of protein kinase C (PKC). Subsequent sustained ischemia then causes renewed stimulation of adenosine A1 receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection. If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P < 0.01). This protection could be blocked by the AT1 receptor blocker losartan (10 microM), but not by the AT2 receptor blocker PD 123319 (10 microM). Polymyxin B (50 microM), a PKC inhibitor, also blocked the protective effect of AII. These observations demonstrated that activation of PKC by AT1 receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the 30 min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort AII's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PKC during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT1 or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.
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PMID:Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. 760 6

KCl-evoked glutamate exocytosis from cerebrocortical synaptosomes can be inhibited by the adenosine A1 receptor agonist cyclohexyladenosine (CHA). Inhibition is associated with a decreased KCl-evoked Ca2+ level elevation, and the effect of the agonist is occluded by prior incubation with the Agelenopsis aperta neurotoxin omega-agatoxin-IVA at 250 nM. The inhibition is suppressed in the presence of 3 nM phorbol dibutyrate (PDBu) or by activation of the protein kinase C (PKC)-coupled metabotropic glutamate receptor by 100 microM (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate [(1S,3R)ACPD]. A tonic inhibition of release by leaked exogenous adenosine can be reversed by adenosine deaminase or by PDBu addition. The CHA-induced inhibition can be enhanced by the PKC inhibitor Ro 31-8220. The mechanism for the suppression of the adenosine A1 receptor-mediated inhibition is distinct from that previously described for the (1S,3R)ACPD-evoked, PKC-mediated, facilitatory pathway, which enhances phosphorylation of the MARCKS protein, 4-aminopyridine-induced action potentials, and release of glutamate because the latter requires at least 100 nM PDBu [or the combination of (1S,3R)ACPD and arachidonic acid] and is not seen following KCl depolarization. Both PKC-mediated pathways may be involved in the presynaptic events associated with the establishment of synaptic plasticity.
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PMID:Protein kinase C-mediated suppression of the presynaptic adenosine A1 receptor by a facilitatory metabotropic glutamate receptor. 761 16

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

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

We investigated species difference in binding of major neurotransmitters and intracellular second messengers in the gerbil brain and the rat brain using receptor autoradiography. [3H]Phorbol 12,13-dibutyrate (PDBu), [3H]inositol 1,4,5-trisphosphate (IP3), [3H]PN200-110, [3H]muscimol, [3H]MK-801, [3H]cyclohexyladenosine (CHA),and [3H]quinuclidinyl benzilate (QNB) were used to label protein kinase C, IP3 receptor, L-type calcium channel, gamma-aminobutyric acidA (GABAA) receptor, N-methyl-D-aspartate (NMDA) receptor, adenosine A1 receptor, and muscarinic cholinergic receptor, respectively. Autoradiographic distributions of the bindings of most neurotransmitters and second messengers were particularly found in the limbic system and basal ganglia in both gerbil and rat brains. However, marked differences in these bindings between the gerbil brain and the rat brain were also recognized in the above regions. In particular, among 7 ligands used, the gerbil had high [3H]PDBu and [3H]CHA binding sites throughout the brain compared to those in the rat brain except for a few areas. By contrast, the rat exhibited high [3H]MK-801 binding sites in various brain regions, as compared with the gerbil brain. Thus, the gerbil differ from the rat with respect to the binding sites of major second messengers and neurotransmitters in the brain. The results may help better elucidate the relationship or species difference between gerbils and rats for neuronal function and behavioral pharmacology.
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PMID:Autoradiographic distribution of neurotransmitter and second messenger system receptors in animal brains. 788 Apr 56


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