Loss of β-adrenergic–stimulated phosphorylation of CaV1.2 channels on Ser1700 leads to heart failure
| Autor: | Dao-Fu Dai, C. Yuan, William A. Catterall, Nastassya West, Haijie Yu, Linghai Yang, Ruth E. Westenbroek, Horacio O. de la Iglesia |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Calcium Channels L-Type Cardiomegaly Biology Motor Activity Muscle hypertrophy Contractility 03 medical and health sciences Internal medicine Calcium-binding protein Receptors Adrenergic beta medicine Animals Myocytes Cardiac Heart Failure Multidisciplinary Ryanodine receptor Calcium channel Calcineurin Calcium-Binding Proteins Troponin I Heart Ryanodine Receptor Calcium Release Channel medicine.disease Cyclic AMP-Dependent Protein Kinases Myocardial Contraction Phospholamban Mice Inbred C57BL Sarcoplasmic Reticulum 030104 developmental biology Endocrinology PNAS Plus Heart failure Calcium |
| Popis: | L-type Ca2+ currents conducted by voltage-gated calcium channel 1.2 (CaV1.2) initiate excitation–contraction coupling in the heart, and altered expression of CaV1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of CaV1.2 channels by mutation of a single PKA site, Ser1700, in the proximal C-terminal domain causes reduced contractile function, cardiac hypertrophy, and heart failure without changes in expression, localization, or function of the CaV1.2 protein in the mutant mice (SA mice). These deficits were aggravated with aging. Dual mutation of Ser1700 and a nearby casein-kinase II site (Thr1704) caused accelerated hypertrophy, heart failure, and death in mice with these mutations (STAA mice). Cardiac hypertrophy was increased by voluntary exercise and by persistent β-adrenergic stimulation. PKA expression was increased, and PKA sites Ser2808 in ryanodine receptor type-2, Ser16 in phospholamban, and Ser23/24 in troponin-I were hyperphosphorylated in SA mice, whereas phosphorylation of substrates for calcium/calmodulin-dependent protein kinase II was unchanged. The Ca2+ pool in the sarcoplasmic reticulum was increased, the activity of calcineurin was elevated, and calcineurin inhibitors improved contractility and ameliorated cardiac hypertrophy. Cardio-specific expression of the SA mutation also caused reduced contractility and hypertrophy. These results suggest engagement of compensatory mechanisms, which initially may enhance the contractility of individual myocytes but eventually contribute to an increased sensitivity to cardiovascular stress and to heart failure in vivo. Our results demonstrate that normal regulation of CaV1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo. |
| Databáze: | OpenAIRE |
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