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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetylcholine muscarinic m2 receptors (m2R) couple to heterotrimeric Gi proteins and activate the Ras/Raf/mitogen-activated protein kinase pathway and phosphatidylinositol 3-kinase in Rat 1a cells. In contrast to the m2R, stimulation of the acetylcholine muscarinic m1 receptor (m1R) does not activate the Ras/Raf/mitogen-activated protein kinase regulatory pathway in Rat 1a cells but rather causes a pronounced inhibition of epidermal growth factor and platelet-derived growth factor receptor activation of Raf. In Rat 1a cells, m1R stimulation of phospholipase C beta and the marked rise in intracellular calcium stimulated cyclic AMP (cAMP) synthesis, resulting in the activation of protein kinase A. Stimulation of protein kinase A inhibited Raf activation in response to growth factors. Platelet-derived growth factor receptor stimulation of phosphatidylinositol 3-kinase activity was not affected by either m1R stimulation or protein kinase A activation in response to forskolin-stimulated cAMP synthesis. GTP loading of Ras in response to growth factors was unaffected by protein kinase A activation but was partially inhibited by carbachol stimulation of the m1R. Therefore, protein kinase A action at the Ras/Raf activation interface selectively inhibited only one branch of the signal transduction network initiated by tyrosine kinases. Specific adenylyl cyclases responding to different signals, including calcium, with enhanced cAMP synthesis will regulate Raf activation in response to Ras.GTP. Taken together, the data indicate that G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase-stimulated mitogenic response pathways.
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PMID:Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity. 813 39

Acetylcholine muscarinic m1 receptors and m2 receptors are predominantly coupled to the heterotrimeric G proteins Gq, 11 and Gi, respectively. Stimulation of the m1 and m2 receptors in different cell types activate the Ras/Raf/MAP kinase pathway. The ability of the m1 receptor to activate the MAP kinase pathway is dependent on the isoforms of adenylyl cyclase expressed in specific cell types. Specific adenylyl cyclases respond to different signals, including calcium and protein kinase C, with increased cAMP synthesis resulting in protein kinase A activation. Stimulation of protein kinase A inhibits Raf and subsequent MAP kinase activation by G protein-coupled receptors and growth factor receptor tyrosine kinases. G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase-stimulated response pathways.
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PMID:Acetylcholine muscarinic receptor regulation of the Ras/Raf/MAP kinase pathway. 1018 97

Coupling of M(2) and M(3) muscarinic receptors to activation of mitogen-activated protein (MAP) kinases and phosphorylation of caldesmon was studied in canine colonic smooth muscle strips in which M(3) receptors were selectively inactivated by N, N-dimethyl-4-piperidinyl diphenylacetate (4-DAMP) mustard (40 nM). ACh elicited activation of extracellular signal-regulated kinase (ERK) 1, ERK2, and p38 MAP kinases in control muscles and increased phosphorylation of caldesmon (Ser(789)), a putative downstream target of MAP kinases. Alkylation of M(3) receptors with 4-DAMP had only a modest inhibitory effect on ERK activation, p38 MAP kinase activation, and caldesmon phosphorylation. Subsequent treatment with 1 microM AF-DX 116 completely prevented activation of ERK and p38 MAP kinase and prevented caldesmon phosphorylation. Caldesmon phosphorylation was blocked by the MAP kinase/ERK kinase inhibitor PD-98509 but not by the p38 MAP kinase inhibitor SB-203580. These results indicate that colonic smooth muscle M(2) receptors are coupled to ERK and p38 MAP kinases. Activation of ERK, but not p38 MAP kinases, results in phosphorylation of caldesmon in vivo, which is a novel function for M(2) receptor activation in smooth muscle.
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PMID:Coupling of M(2) muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle. 1071 63

Phosphorylation of h-caldesmon has been proposed to regulate airway smooth muscle contraction. Both extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases phosphorylate h-caldesmon in vitro. To determine whether both enzymes phosphorylate caldesmon in vivo, phosphorylation-site-selective antibodies were used to assay phosphorylation of MAP kinase consensus sites. Stimulation of cultured tracheal smooth muscle cells with ACh or platelet-derived growth factor increased caldesmon phosphorylation at Ser789 by about twofold. Inhibiting ERK MAP kinase activation with 50 microM PD-98059 blocked agonist-induced caldesmon phosphorylation completely. Inhibiting p38 MAP kinases with 25 microM SB-203580 had no effect on ACh-induced caldesmon phosphorylation. Carbachol stimulation increased caldesmon phosphorylation at Ser789 in intact tracheal smooth muscle, which was blocked by the M(2) antagonist AF-DX 116 (1 microM). AF-DX 116 inhibited carbachol-induced isometric contraction by 15 +/- 1.4%, thus dissociating caldesmon phosphorylation from contraction. Activation of M(2) receptors leads to activation of ERK MAP kinases and phosphorylation of caldesmon with little or no functional effect on isometric force. P38 MAP kinases are also activated by muscarinic agonists, but they do not phosphorylate caldesmon in vivo.
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PMID:Phosphorylation of caldesmon by ERK MAP kinases in smooth muscle. 1075 21

Astrocytes constitute the most abundant cell type in the nervous system. Under physiological conditions, they respond to the stimuli to which neurons are also responsive. The use of astrocytoma cell lines with well-defined morphological and functional markers has been helpful for addressing the mechanisms of signal transduction that operate in the nervous system. On the basis of the effects produced by agonists of different types of receptor (muscarinic ACh receptors, thrombin receptors, phospholipases A2 receptors and tumor necrosis factor alpha receptors), several different transcriptional programs that involve the MAP kinase-cytosolic phospholipase A2 system and the transcription factor NF-kappaB have been described.
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PMID:Cytosolic phospholipase A2 and the distinct transcriptional programs of astrocytoma cells. 1083 95

In canine colon, M2/M3 muscarinic receptors are coupled to extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. We tested the hypothesis that this coupling is mediated by enzymes of the phosphatidylinositol (PI) 3-kinase family. RT-PCR and Western blotting demonstrated expression of two isoforms, PI 3-kinase-alpha and PI 3-kinase-gamma. Muscarinic stimulation of intact muscle strips (10 microM ACh) activated PI 3-kinase-gamma, ERK and p38 MAP kinases, and MAP kinase-activated protein kinase-2, whereas PI 3-kinase-alpha activation was not detected. Wortmannin (25 microM) abolished the activation of PI 3-kinase-gamma, ERK, and p38 MAP kinases. MAP kinase inhibition was a PI 3-kinase-gamma-specific effect, since wortmannin did not inhibit recombinant activated murine ERK2 MAP kinase, protein kinase C, Raf-1, or MAP kinase kinase. In cultured muscle cells, newborn calf serum (3%) activated PI 3-kinase-alpha and PI 3-kinase-gamma isoforms, ERK and p38 MAP kinases, and stimulated chemotactic cell migration. Using wortmannin and LY-294002 to inhibit PI 3-kinase activity and PD-098059 and SB-203580 to inhibit ERK and p38 MAP kinases, we established that these enzymes are functionally important for regulation of chemotactic migration of colonic myocytes.
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PMID:Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle. 1091 1

The purpose of this study was to determine whether Src tyrosine kinases are one of the signaling intermediaries linking M(2) receptor stimulation to extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) in cultures of canine colonic smooth muscle cells (CSMC). RT-PCR studies demonstrate expression of multiple Src tyrosine kinases, including Src, Fyn, and Yes, in CSMC. Muscarinic stimulation of CSMC with 10 microM ACh results in a twofold increase in Src activity within 10 min but does not increase the activity of Fyn. Treatment with the M(2) antagonist AF-DX 116 (10 microM) blocks ACh-stimulated Src activation in primary CSMC cultures that express both M(2) and M(3) receptors and in first-passage CSMC cultures that express predominantly M(2) receptors. Alkylation of M(3) receptors with 100 nM N,N-dimethyl-4-piperidinyl diphenylacetate mustard has no effect on Src activity. Treatment with the pyrazolopyrimidine Src inhibitor PP1 (10 microM) or AF-DX 116 (10 microM) blocks ACh-stimulated ERK phosphorylation. Together these results indicate that M(2) receptors are coupled to Src tyrosine kinase and subsequent activation of ERK in cultured CSMC.
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PMID:Coupling of M(2) muscarinic receptors to Src activation in cultured canine colonic smooth muscle cells. 1175 Nov 58

Reactive oxygen species (ROS) have been implicated in the pathogenesis of muscle dysfunction in acute inflammatory processes. The aim of these studies was to determine the effects of ROS on gallbladder muscle function in vitro. Single muscle cells were obtained by enzymatic digestion. H(2)O(2) (70 microM) caused maximal contraction of up to 14% and blocked the response to CCK-8, ACh, and KCl. It did not affect the contractions induced by guanosine 5'-O-(3-thiotriphosphate), diacylglycerol, and inositol 1,4,5-trisphosphate that circumvent membrane receptors. The contraction induced by H(2)O(2) was inhibited by AACOCF(3) [cytosolic phospholipase A(2) (cPLA(2)) inhibitor], indomethacin (cyclooxygenase inhibitor), chelerythrine [protein kinase C (PKC) inhibitor], or PD-98059 [mitogen-activated protein kinase (MAPK) inhibitor]. H(2)O(2) also reduced the CCK receptor binding capacity from 0.36 +/- 0.05 pmol/mg protein (controls) to 0.17 +/- 0.03 pmol/mg protein. The level of lipid peroxidation as well as the PGE(2) content was significantly increased after H(2)O(2) pretreatment. Unlike superoxide dismutase, the free radical scavenger catalase prevented the H(2)O(2) induced contraction, and its inhibition of the CCK-8 induced contraction. It is concluded that ROS cause damage to the plasma membrane of the gallbladder muscle and contraction through the generation of PGE(2) induced by cPLA(2)-cyclooxygenase and probably mediated by the PKC-MAPK pathway.
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PMID:Reactive oxygen species (H(2)O(2)): effects on the gallbladder muscle of guinea pigs. 1180 51

Acetylcholine release from cholinergic neurons regulates pancreatic exocrine function through pathways that are still under investigation. Pancreatic AR42J acinar cells were studied to determine intracellular calcium ([Ca(2+)](i)) release, enzyme activation, and gene expression in response to the acetylcholine analog carbachol (CCh). CCh stimulated dose-dependent increases in [Ca(2+)](i) that were inhibited by atropine and by specific inhibitors to the muscarinic receptor subtypes m1 and m3. Polymerase chain reaction analysis was performed, which sequenced products corresponding to the m1 and m3 receptor subtypes but not the m2 subtype. CCh also stimulated mitogen-activated protein kinase activity. CCh induced time-and dose-dependent increases in the c-fos and c-jun early-response genes, which were blocked by m1 and m3 inhibition but not by m2 inhibition.
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PMID:Cholinergic stimulation of rat acinar cells increases c-fos and c-jun expression via a mitogen-activated protein kinase-dependent pathway. 1208 6

Obesity is often associated with cardiovascular and metabolic disorders such as hypertension and hyperglycemia. Leptin, a protein product of the obese gene, regulates satiety and energy expenditure through its receptors in the hypothalamus. Recent studies have shown that leptin has extrahypothalamic and peripheral actions. The presence of leptin receptors has been reported in the adrenal medulla. In the present study, we examined the effects of leptin on catecholamine synthesis in cultured bovine adrenal medullary cells. Leptin (3-30 nM) caused a significant increase in (14)C-catecholamine synthesis from [(14)C] tyrosine, but not from [(14)C] DOPA. Incubation of cells with leptin resulted in an activation and phosphorylation of tyrosine hydroxylase. Leptin caused a transient activation of mitogen-activated protein kinases (MAPKs). U0126, an inhibitor of MAPK kinase, abolished the effect of leptin on (14)C-catecholamine synthesis. High concentrations of leptin (10-100 nM) produced an increase in intracellular Ca(2+) concentration, which was blocked by Cd(2+), an inhibitor of voltage-dependent Ca(2+) channels. Concurrent treatment of cells with leptin (10 nM) and acetylcholine (0.3 mM) potently enhanced the stimulatory effect of acetylcholine on (14)C-catecholamine synthesis. Leptin, however, failed to enhance the stimulatory effect of acetylcholine on the phosphorylation and activity of tyrosine hydroxylase. Acetylcholine (0.3 mM) decreased the intracellular pH (pHi). Leptin (10 nM) affected neither the basal pHi nor the acetylcholine-induced fall in pHi. These findings suggest that leptin phosphorylates and activates tyrosine hydroxylase and subsequently stimulates catecholamine synthesis through MAPK and probably Ca(2+) pathways in the adrenal medulla.
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PMID:Regulation of catecholamine synthesis by leptin. 1243 73


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