Journal article
Loss of β-adrenergic-stimulated phosphorylation of CaV1.2 channels on Ser1700 leads to heart failure
Proceedings of the National Academy of Sciences - PNAS, Vol.113(49), pp.E7976-E7985
12/06/2016
DOI: 10.1073/pnas.1617116113
PMCID: PMC5150375
PMID: 27864509
Abstract
L-type Ca
currents conducted by voltage-gated calcium channel 1.2 (Ca
1.2) initiate excitation-contraction coupling in the heart, and altered expression of Ca
1.2 causes heart failure in mice. Here we show unexpectedly that reducing β-adrenergic regulation of Ca
1.2 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 Ca
1.2 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 Ca
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 Ca
1.2 channels by phosphorylation of Ser1700 in cardiomyocytes is required for cardiovascular homeostasis and normal physiological regulation in vivo.
Details
- Title: Subtitle
- Loss of β-adrenergic-stimulated phosphorylation of CaV1.2 channels on Ser1700 leads to heart failure
- Creators
- Linghai Yang - Department of Pharmacology, University of Washington, Seattle, WA 98195Dao-Fu Dai - Department of Pathology, University of Washington, Seattle, WA 98195Can Yuan - Department of Pharmacology, University of Washington, Seattle, WA 98195Ruth E Westenbroek - Department of Pharmacology, University of Washington, Seattle, WA 98195Haijie Yu - Department of Pharmacology, University of Washington, Seattle, WA 98195Nastassya West - Department of Biology, University of Washington, Seattle, WA 98195Horacio O de la Iglesia - Department of Biology, University of Washington, Seattle, WA 98195William A Catterall - Department of Pharmacology, University of Washington, Seattle, WA 98195; wcatt@uw.edu
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.113(49), pp.E7976-E7985
- DOI
- 10.1073/pnas.1617116113
- PMID
- 27864509
- PMCID
- PMC5150375
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences; United States
- Grant note
- DOI: 10.13039/100000050, name: HHS | NIH | National Heart, Lung, and Blood Institute, award: HL085372
- Language
- English
- Date published
- 12/06/2016
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Radiation Oncology
- Record Identifier
- 9984047886102771
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