Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High doses of propranolol inhibit phosphatidate phosphohydrolase (PAP) activity in intact cells, thus blocking metabolism of phosphatidic acid (PA), product of the phospholipase D (PLD) reaction. Vasopressin and phorbol ester activate PLD and ERK (extracellular signal-regulated protein kinase) mitogen-activated protein kinases in A7r5, a rat vascular smooth muscle cell line. Propranolol increased PA levels in intact A7r5 cells and inhibited cytosolic PAP and membrane calcium-independent phospholipase A2 but did not activate PLD or enhance agonist-induced PA accumulation. Incubation of cells with 200 microM propranolol for 10-45 min markedly elevated PA but caused only partial activation of ERKs. Propranolol and other lipophilic amines caused a time- and dose-dependent detachment of cells from their substrate. These results confirm that elevation of PA is not a strong signal for ERK activation and emphasize that caution should be exercised in using propranolol as a PAP inhibitor in intact cells.
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PMID:Effects of propranolol on phosphatidate phosphohydrolase and mitogen-activated protein kinase activities in A7r5 vascular smooth muscle cells. 972 Jul 64

Beta-blockers have beneficial effects in heart failure, although the underlying mechanism is unknown. Beta2-adrenoceptors, however, are proportionally higher in the failing human heart. This study shows several clinically used beta-blockers are agonists at the human beta2-adrenoceptor. Although these agonist effects were small at the cAMP level, they were substantial at the level of cAMP response element (CRE)-mediated gene transcription. Some of the effects of "beta-blockers" seen in heart failure may be related to the beta2-agonist actions of these compounds. CRE-gene transcription responses to beta2-agonists, forskolin, and cAMP-analogs were sensitive to p42/44-mitogen-activated protein (MAP) kinase pathway inhibitors. p42/44-MAP kinase activation was also shown directly by western blotting and enzyme-linked immunosorbent assay techniques. N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89; a protein kinase A inhibitor) stimulated cAMP accumulation and CRE gene transcription via the beta2-adrenoceptor at concentrations at which protein kinase A was inhibited, providing evidence for an alternative pathway. Propranolol, however, produced paradoxical effects; it reduced basal cAMP accumulation (via beta2-mediated inverse agonism) but stimulated beta2-mediated CRE gene transcription. This cannot be explained by a sequential pathway from Gs-adenylyl cyclase-cAMP to CRE binding protein phosphorylation. Both responses to propranolol were insensitive to pertussis toxin, thus excluding Gi-protein involvement. Propranolol CRE gene transcription responses were attenuated by p42/44-MAP kinase inhibitors and propranolol was also found to directly stimulate the p42/44-MAP kinase pathway. Studies of inositol phosphate accumulation and of protein kinase C or Rho kinase inhibitors on CRE-gene transcription provided no evidence for Gq/11 or G12/13 involvement. These data suggest that propranolol can simultaneously act as an inverse agonist through a Gs-coupled mechanism while stimulating the p42/44-MAP kinase pathway through an alternative G-protein-independent mechanism.
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PMID:Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling. 1464 66

Candida albicans (C. albicans) is known as an opportunistic pathogen that changes from a yeast form to a hyphae form in response to various outside environmental signals. The addition of propranolol inhibited hyphae formation of C. albicans. Propranolol inhibited the expression of agglutinin like sequence 3 (ALS3) and ALS8mRNA, which are regulated by the cAMP-EFG1 pathway in C. albicans. Propranolol did not affect the expression of CST20, HST7 or CPH1mRNA, which are components of the mitogen-activated protein (MAP) kinase cascade in C. albicans. The expression of CYR1mRNA, which encodes adenylate cyclase of C. albicans, was not affected by propranolol. These findings indicated that the interruption of hyphae formation by propranolol is caused by inhibition of the cAMP-EFG1 pathway, but not effects on the MAP kinase cascade.
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PMID:Effect of propranolol on hyphae formation signal in Candida albicans. 1912 94