| General information | Literature | Expression | Regulation | Mutation | Interaction |
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Basic Information |
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|---|---|
Gene ID | 5566 |
Name | PRKACA |
Synonymous | PKACA;protein kinase, cAMP-dependent, catalytic, alpha;PRKACA;protein kinase, cAMP-dependent, catalytic, alpha |
Definition | PKA C-alpha|cAMP-dependent protein kinase catalytic subunit alpha|protein kinase A catalytic subunit |
Position | 19p13.1 |
Gene type | protein-coding |
Source | Count: PRKACA; 5566 |
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Sentence |
Abstract |
| Recent reports of elevated transient receptor potential (TRP) calcium channels TRP3 and TRP6 in PA SMCs from IPAH patients indicated that inhibition of these channels can repress the heightened proliferation observed in SMCs. Inhibition of PKA or activation of cAMP seem to have a similar effect. | The combinations of the endothelin-1 receptor antagonists bosentan or ambrisentan with the phosphodiesterase 5 inhibitors sildenafil or tadalafil are current standard therapies of advanced pulmonary arterial hypertension. However, these drugs have a number of drug interactions. Changes of bosentan pharmacokinetics by sildenafil are attributed to reduced hepatic uptake as a consequence of inhibition of organic anion transporting polypeptides. We therefore tested in vitro the hypothesis that sildenafil and tadalafil reduce the enzyme- and transporter-inducing effects of bosentan or ambrisentan by preventing cellular access. Although intracellular concentrations of bosentan and ambrisentan (measured by high pressure liquid chromatography coupled with tandem mass-spectrometry) after four days of incubation of LS180 cells were lower when sildenafil or tadalafil were present, quantification of mRNA expression in these cells by real-time reverse transcription polymerase chain reaction revealed that bosentan and ambrisentan-mediated induction was stable or even increased in combination with sildenafil or tadalafil. For the drug transporter P-glycoprotein this was confirmed at the protein and functional level with highly significant correlations between P-gp mRNA, protein, and function. Moreover, using a reporter gene assay in LS180 cells, our study demonstrates for the first time that tadalafil is a potent, ambrisentan a weak, and sildenafil no activator of pregnane X receptor. In conclusion, our study demonstrates that although sildenafil and tadalafil indeed reduce intracellular concentrations of bosentan and ambrisentan in LS180 cells, they do not mitigate the inducing effects of these endothelin-1 receptor antagonists.CI - Copyright (c) 2012 Elsevier Inc. All rights reserved. |