Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, membrane depolarization and multiple neurotransmitters (5-HT, acetylcholine, histamine, norepinephrine, epinephrine, glutamate, and ATP) were tested for the ability to elevate the intracellular free Ca2+ concentration ([Ca2+]i) in mouse HT4 neuroblastoma cells. Apart from ATP, none of the treatments gave rise to a detectable Ca2+ response, no matter whether the cells were subjected to temperature-induced neuronal differentiation. Our results provide pharmacological evidence for the co-existence in HT4 cells of both P2X and P2Y receptors, the activation of which by ATP led to Ca2+ influx and Ca2+ release, respectively. The P2Y receptor was found to couple to more than one type of G protein in the signaling pathway, causing the activation of phospholipase C (PLC) and Ca2+ mobilization from intracellular stores. cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) attenuated ATP-evoked [Ca2+]i elevations in different ways. However, no correlation was identified between neuronal differentiation and the ATP-evoked Ca2+ responses in HT4 cells. This work indicates that HT4 cells can serve as a good model to study P2 purinoceptor-associated signaling pathways.
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PMID:Evoked intracellular Ca2+ elevations in HT4 neuroblastoma cells. 1206 Aug 15

The effect of external ATP on intracellular pH (pH(i)) was investigated using a pH imaging system in a human bronchial epithelial cell line (16HBE14o-) loaded with BCECF-AM. The steady-state pH(i) of 16HBE14o- epithelial monolayers was 7.137 +/- 0.027 (n = 46). Apical addition of ATP (10(-4) M) to epithelial monolayers induced a rapid and sustained pH(i) decrease of 0.164 +/- 0.024 pH units (n = 17; P < 0.001). The intracellular acidification was rapidly reversed upon removal of external ATP. In contrast, the non-hydrolysable ATP analogue AMP-PNP did not produce any significant change in pH(i). Inhibition of purinoreceptors by suramin did not affect the acidification induced by apical ATP. Inhibition of Na+-H+ exchange by apical Na+ removal or addition of amiloride (0.5 mM) reduced the apical ATP-induced pH(i) decrease, suggesting the involvement of a Na+-H+ exchanger or surface pH effects on the ATP-induced pH(i) response. Inhibitors of proton channels such as ZnCl2 (10(-4) M) also partially inhibited the ATP response. The pH(i) response to ATP was dependent on the external pH (pH(o)), with increasing acidification produced at lower pH(o) values. Neither the basal pH(i) nor the ATP-induced intracellular acidification was affected by thapsigargin (a Ca2+-ATPase inhibitor), chelerythrine chloride (a protein kinase C (PKC) inhibitor), RpcAMP (a protein kinase A (PKA) inhibitor) or PMA (a PKC activator). Therefore, the intracellular acidification of human bronchial epithelial cells induced by apical ATP does not involve signalling via Ca2+, PKC or PKA nor binding to a purinoreceptor. We interpret the effect of ATP to produce an intracellular acidification as a three step process: activation of H+ channels, inhibition of Na+-H+ exchange and influx of protonated ATP.
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PMID:Cellular mechanisms for apical ATP effects on intracellular pH in human bronchial epithelium. 1218 Dec 78

The present study was designed to assess the effects of adenosine triphosphate (ATP) on hippocampal neurotransmissions under the normal and hypoxic/hypoglycemic conditions. ATP reversely depressed population spikes (PSs), which were monitored in the dentate gyrus of guinea pig hippocampal slices, in a dose-dependent manner at concentrations ranged from 0.1 micro M to 1 mM. A similar depression was obtained with the P(2) receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP), and the effect was inhibited by the P(2) receptor antagonists, suramin and PPADS. The inhibitory action of ATP or alpha,beta-MeATP was inhibited by the gamma-aminobutyric acid(A) (GABA(A)) receptor antagonist, bicuculline, but it was not affected by theophylline, a broad inhibitor of adenosine (P(1)) receptors, tetraethylammonium, a broad inhibitor of K(+) channels, or ecto-protein kinase inhibitors. ATP or alpha,beta-MeATP enhanced GABA release from guinea pig hippocampal slices, that was inhibited by deleting extracellular Ca(2+) or in the presence of tetrodotoxin, while ATP had no effect on GABA release from cultured rat hippocampal astrocytes or postsynaptic GABA-gated channel currents in cultured rat hippocampal neurons. Twenty-minutes deprivation of glucose and oxygen from extracellular solution abolished PSs, the amplitude recovering to about 30% of basal levels 50 min after returning to normal conditions. ATP or alpha,beta-MeATP accelerated the recovery after hypoxic/hypoglycemic insult (approximately 80% of basal levels). Adenosine diphosphate and adenosine monophosphate accelerated the recovery, but to a much lesser extent, and adenosine had no effect. The results of the present study thus suggest that ATP inhibits neuronal activity by enhancing neuronal GABA release via a P(2) receptor, perhaps a P2X receptor, thereby protecting against hypoxic/hypoglycemic perturbation of hippocampal neurotransmission.
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PMID:Adenosine triphosphate accelerates recovery from hypoxic/hypoglycemic perturbation of guinea pig hippocampal neurotransmission via a P(2) receptor. 1236 1

Astrocytes are involved in normal and pathological brain functions, where they become activated and undergo reactive gliosis. Astrocytes have been shown to respond to extracellular nucleotides via the activation of P2 receptors, either G protein-coupled P2Y receptors or P2X receptors that are ligand-gated ion channels. In this study, we have examined the manner in which activation of the P2X(7) nucleotide receptor, an extracellular ATP-gated ion channel expressed in astrocytes, can lead to the phosphorylation of ERK1/2. Results showed that the P2X(7) receptor agonist 2',3'-O-(4-benzoyl)benzoyl-ATP induced ERK1/2 phosphorylation in human astrocytoma cells overexpressing the recombinant rat P2X(7) receptor (rP2X(7)-R), a response that was inhibited by the P2X(7) receptor antagonist, oxidized ATP. Other results suggest that rP2X(7)-R-mediated ERK1/2 phosphorylation was linked to the phosphorylation of the proline-rich/Ca(2+)-activated tyrosine kinase Pyk2, c-Src, phosphatidylinositol 3'-kinase, and protein kinase Cdelta activities and was dependent on the presence of extracellular Ca(2+). These results support the hypothesis that the P2X(7) receptor and its signaling pathways play a role in astrocyte-mediated inflammation and neurodegenerative disease.
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PMID:Mechanisms of P2X7 receptor-mediated ERK1/2 phosphorylation in human astrocytoma cells. 1252 54

Nucleotides can activate ionotropic P2X receptors that induce calcium-responses in rat midbrain synaptosomes. In this report, we show that ATP elicits Ca(2+) responses producing a monophasic dose-response curve with an EC(50) value of 24.24+/-1.42 micro M. In the presence of gamma-aminobutyric acid (GABA), the ATP dose-response curve becomes biphasic with EC(50) values of 3.69+/-0.44 nM and 59.65+/-8.32 micro M. Moreover, the maximal calcium response induced by ATP is 52.1% higher than the control. This effect is mimicked or blocked by the specific GABA(B) receptor agonist and antagonist, baclofen and saclofen, respectively. Presynaptic GABA(B) receptors, identified by immunocytochemistry are present in 62% of the total synaptosomal population. Adenylate cyclase and protein kinase A cascades are involved in the potentiatory effects mediated by baclofen and their activation or inhibition modifies calcium signalling and synaptosomal cAMP levels. The potentiatory action of baclofen was confirmed by microfluorimetry performed on single synaptic terminals. In its presence, 86% of the terminals responding to 100 micro M ATP, are also able to respond to nanomolar concentrations (100 nM) of this nucleotide. This potentiatory effect is reduced to 32% in the presence of pertussis toxin. Our data suggest that the activity of P2X receptors is modulated by GABA(B) receptors in midbrain synaptosomes.
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PMID:GABAB receptor-mediated presynaptic potentiation of ATP ionotropic receptors in rat midbrain synaptosomes. 1260 91

Corelease of ATP with ACh from motor endings suggests a physiological role for ATP in synaptic transmission. We previously showed that, on skeletal muscle, ATP directly inhibited ACh release via presynaptic P2 receptors. The receptor identification (P2X or P2Y) and its transduction mechanism remained, however, unknown. In the present study using the voltage-clamp technique we analyzed the properties of presynaptic ATP receptors and subsequent effector mechanisms. ATP or adenosine presynaptically depressed multiquantal end-plate currents, with longer latency for ATP action. ATPgammaS, agonist at P2X receptors, or Bz-ATP, agonist at P2X7 receptors, were ineffective. The action of ATP was prevented by suramin and unchanged by PPADS or TNP-ATP, antagonists of P2X receptors, or RB-2, a blocker of certain P2Y receptors. The depressant action of ATP was reproduced by UTP, metabotropic P2Y receptor agonist. Pertussis toxin (PTX), antagonist of Gi/o-proteins, and inhibitors of phosphatidylcholine specific PLC (D609) and PKC (staurosporine or chelerythrine) prevented the effect of ATP while blockers of PLA2 (OBAA) and COX (aspirin or indomethacin) attenuated it. Inhibitors of phosphatidylinositide-specific PLC (U73122), guanylylcyclase (ODQ), PKA (Rp-cAMPS) or PLD (1-butanol) did not affect the action of ATP. No inhibitor of second messengers (except PTX) changed the action of adenosine. Our data indicate, for motor nerve endings, the existence of inhibitory P2Y receptors coupled to multiple intracellular cascades including phosphatidylinositide-specific PLC/PKC/PLA2/COX. This divergent presynaptic P2 signalling (unlike the single effector mechanism for P1 receptors) could provide feedback inhibition of transmitter release and perhaps be involved in presynaptic plasticity.
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PMID:Distinct receptors and different transduction mechanisms for ATP and adenosine at the frog motor nerve endings. 1295 24

Electrophysiological recordings were used to investigate the effects of ATP analogues on theta-burst-induced long-term potentiation (LTP) in rat hippocampal slices. alpha,beta-Methylene ATP (alpha,beta-MeATP; 20 microM) decreased LTP from 36+/-9% to 17+/-5%, an effect prevented by adenosine A(1) receptor blockade in accordance with the localised catabolism of ATP analogues into adenosine, leading to adenosine A(1) receptor activation. Thus, to probe the role of extracellular ATP, all experiments were performed with the A(1) receptor selective antagonist, 1,3-dipropyl-8-cyclopentylxanthine (50 nM). In these conditions, alpha,beta-MeATP or 5'-adenylylimido-diphosphate (beta,gamma-ImATP; 20 microM) facilitated LTP by 120%, an effect prevented by the P2 receptor antagonists, pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS; 20 microM) or suramin (75 microM), as well as by the P2X(1/3)-selective antagonist 8-(benzamido)naphthalene-1,3,5-trisulfonate (10 microM). The facilitations of LTP by either alpha,beta-MeATP or beta,gamma-ImATP (20 microM) were also prevented by both 4-(2-[7-amino-2-(2-furyl(1,2,4)-triazolo(2,3a)-(1,3,5)triazin-5-yl-amino]ethyl)phenol (50 nM) or 7-2(-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (50 nM), antagonists of facilitatory adenosine A(2A) receptors, were occluded by the A(2A) receptor agonist, CGS 21680 (10 nM) and were prevented by the protein kinase C inhibitor, chelerythrine (6 microM) and unaffected by the protein kinase A inhibitor, H89 (1 microM). Furthermore, beta,gamma-ImATP (20 microM) enhanced [(3)H]adenosine outflow from rat hippocampal slices by nearly 150%, an effect prevented by PPADS (20 microM) or suramin (75 microM). The adenosine transport inhibitors, nitrobenzylthioinosine (5 microM) and dipyridamole (10 microM) also prevented beta,gamma-ImATP (20 microM)-induced [(3)H]adenosine outflow and facilitation of LTP. These results suggest that ATP analogues facilitate LTP through P2 receptor activation that mainly triggers adenosine release leading to the activation of adenosine A(2A) receptors.
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PMID:Purinergic P2 receptors trigger adenosine release leading to adenosine A2A receptor activation and facilitation of long-term potentiation in rat hippocampal slices. 1459 53

Receptor agonists that initiate fluid secretion in salivary gland epithelial cells also increase protein phosphorylation. To assess contributions of tyrosine phosphorylation to secretion, changes in muscarinic receptor-initiated secretion (estimated from sodium pump-dependent increases in oxygen consumption) were measured in parotid acinar cells exposed to tyrosine kinase inhibitors. However, like the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenyl hydrazone, tyrphostins AG10 and AG18 increased the rate of oxygen consumption and reduced cellular ATP by approximately 90% in the absence of the muscarinic agonist carbachol, indicating that these tyrphostins uncouple mitochondria. Exposure of isolated mitochondria to five structurally related tyrphostins demonstrated that their relative potencies as uncouplers differed from their in vitro kinase-inhibitory potencies due to different molecular requirements for the two effects. AG10 and AG18 blocked parotid phosphorylation events only at concentrations that reduced ATP content. The tyrosine kinase inhibitor genistein reduced ATP content by 15-20% and weakly uncoupled isolated mitochondria, but its inhibition of carbachol-mediated protein kinase Cdelta tyrosine phosphorylation and ERK1/2 activation appeared attributable to blocking tyrosine kinases directly. Carbachol itself rapidly reduced ATP content by 15-20%. Carbachol, 3'-O-(4-benzoyl)benzoyl adenosine 5'-triphosphate (P2X(7) receptor agonist), AG10, AG18, and carbonyl cyanide p-trifluoromethoxyphenyl hydrazone rapidly activated the fuel sensor AMP-activated protein kinase (AMPK); however, only AMPK activation by carbachol and BzATP was due to sodium pump stimulation. AG10 and AG18 also activated AMPK and/or uncoupled mitochondria in PC12, HeLa, and HEK293 cells. These studies demonstrate that some tyrosine kinase inhibitors produce cellular effects that are mechanistically different from their primary in vitro characterizations and, as do salivary secretory stimuli, promote rapid metabolic alterations that initiate secondary signaling events.
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PMID:Evidence that tyrphostins AG10 and AG18 are mitochondrial uncouplers that alter phosphorylation-dependent cell signaling. 1468 71

The mechanism of mechanical hyperalgesia in inflammation might involve a 'mechanochemical' process whereby stretch evokes the release of adenosine 5'-triphosphate (ATP) from the damaged tissue that then excites nearby primary sensory nerve terminals. In the present study, phosphorylated extracellular signal-regulated protein kinase (pERK) immunoreactivity was used as a marker indicating functional activation of primary afferent neurons to examine the P2X receptor-mediated noxious response in DRG neurons in a rat model of peripheral inflammation. We found that very few pERK-labeled DRG neurons were detected in normal rats after alpha, beta methylene-ATP (alphabetame-ATP) intraplantar injection. However, a number of DRG neurons were labeled for pERK after alphabetame-ATP injection to the complete Freund's adjuvant (CFA) induced inflamed paw. Seventy-three percent of pERK-labeled DRG neurons co-expressed the P2X3 receptor. After mechanical noxious stimulation to the hind paw of CFA-inflamed rats, we found many more pERK-labeled neurons compared to those in the normal rats. Administration of the P2X3 receptor antagonists, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid or 2'- (or 3')-O-(trinitrophenyl)adenosine 5'-triphosphate (TNP-ATP), significantly decreased the mechanical stimulation-evoked pERK labeling in CFA-inflamed rats, but not in normal rats. We also found the recruitment of neurons with myelinated A fibers labeled for pERK in CFA-inflamed rats, which was reversed by P2X3 receptor antagonists. Moreover, TNP-ATP dose dependently reduced the mechanical hypersensitivity of CFA rats. These data suggest that the P2X receptors in primary afferent neurons increase their activity with enhanced sensitivity of the intracellular ERK signaling pathway during inflammation and then contribute to the hypersensitivity to mechanical noxious stimulation in the inflammatory state.
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PMID:Contribution of sensitized P2X receptors in inflamed tissue to the mechanical hypersensitivity revealed by phosphorylated ERK in DRG neurons. 1503 Sep 45

In the prostatic portion of rat vas deferens, the non-selective adenosine receptor agonist NECA (0.1-30 microM), but not the A(2A) agonist CGS 21680 (0.001-10 microM), caused a facilitation of electrically evoked noradrenaline release (up to 43 +/- 4%), when inhibitory adenosine A(1) receptors were blocked. NECA-elicited facilitation of noradrenaline release was prevented by the A(2B) receptor-antagonist MRS 1754, enhanced by preventing cyclic-AMP degradation with rolipram, abolished by the protein kinase A inhibitors H-89, KT 5720 and cyclic-AMPS-Rp and attenuated by the protein kinase C inhibitors Ro 32-0432 and calphostin C. The adenosine uptake inhibitor NBTI also elicited a facilitation of noradrenaline release; an effect that was abolished by adenosine deaminase and attenuated by MRS 1754, by inhibitors of the extracellular nucleotide metabolism and by blockade of alpha(1)-adrenoceptors and P2X receptors with prazosin and NF023, respectively. It was concluded that adenosine A(2B) receptors are involved in a facilitation of noradrenaline release in the prostatic portion of rat vas deferens that can be activated by adenosine formed by extracellular catabolism of nucleotides. The receptors seem to be coupled to the adenylyl cyclase-protein kinase A pathway but activation of the protein kinase C by protein kinase A, may also contribute to the adenosine A(2B) receptor-mediated facilitation of noradrenaline release.
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PMID:Coupling to protein kinases A and C of adenosine A2B receptors involved in the facilitation of noradrenaline release in the prostatic portion of rat vas deferens. 1522


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