Abstract 049: Phosphodiesterase-3a Catalytic-domain Mutation and Hypertension
| العنوان: | Abstract 049: Phosphodiesterase-3a Catalytic-domain Mutation and Hypertension |
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| المؤلفون: | Sylvia Bähring, Friedrich C. Luft, Enno Klussmann, Atakan Aydin, Carolin Schächterle |
| المصدر: | Hypertension. 68 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Genetics, Chemistry, Mutation (genetic algorithm), Internal Medicine, Phosphodiesterase, Domain (software engineering) |
| الوصف: | We recently discovered phosphodiesterase-3A (PDE3A) mutations causing a 50 mm Hg increase in blood pressure and stroke >50 years, as the first non-salt form of Mendelian genetic hypertension, autosomal-dominant hypertension with brachydactyly (HTNB). The mutations cause increased PDE3A phosphorylation and higher cAMP affinity. We now have found a completely different PDE3A mutation causing a similar syndrome in a New Zealand pedigree. The mutation resides in the enzyme’s catalytic domain, results in an arginine-to-cysteine substitution, and represents a more direct mechanism of PDE3A activation. For Michaelis-Menten kinetics of cAMP hydrolysis, we transfected HEK293 cells transiently expressing Flag-tagged versions of PDE3A1, PDE3A2, or PDE3A3 mutant vs. wildtype and stimulated with forskolin and phorbol-12-myristate-13-acetate (PMA) to enhance intrinsic phosphorylation. Vmax and Km (Michaelis constant) were calculated using GraphPad Prism software to reveal the maximum cAMP turnover rate at saturated substrate concentration and the affinity of cAMP to wildtype and mutated PDE3A1, PDE3A2 and PDE3A3. For PDE3A1 hydrolytic activity (triplicate), we observed: Vmax Km Wildtype 7.5 340 Wildtype+forskolin/PMA 7.2 203 Mutant 6.6 116 Mutant+forskolin/PMA 6.3 81 The dramatically lower Km of mutant PDE3A indicates a substantially greater affinity for cAMP consistent with gain-of-function. These data underscore the importance of PDE3A to high blood pressure by means of a different, novel genetic mechanism directly implicating the catalytic domain. |
| تدمد: | 1524-4563 0194-911X |
| DOI: | 10.1161/hyp.68.suppl_1.049 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::e43f6a277ad2bb576cf2beb960c14010 https://doi.org/10.1161/hyp.68.suppl_1.049 |
| رقم الانضمام: | edsair.doi...........e43f6a277ad2bb576cf2beb960c14010 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15244563 0194911X |
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| DOI: | 10.1161/hyp.68.suppl_1.049 |