Journal article
Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure
Circulation research, Vol.119(8), pp.931-943
09/30/2016
DOI: 10.1161/CIRCRESAHA.116.308964
PMCID: PMC5307331
PMID: 27576469
Abstract
In heart failure, myofilament proteins display abnormal phosphorylation, which contributes to contractile dysfunction. The mechanisms underlying the dysregulation of protein phosphorylation on myofilaments is not clear.
This study aims to understand the mechanisms underlying altered phosphorylation of myofilament proteins in heart failure.
We generate a novel genetically encoded protein kinase A (PKA) biosensor anchored onto the myofilaments in rabbit cardiac myocytes to examine PKA activity at the myofilaments in responses to adrenergic stimulation. We show that PKA activity is shifted from the sarcolemma to the myofilaments in hypertrophic failing rabbit myocytes. In particular, the increased PKA activity on the myofilaments is because of an enhanced β2 adrenergic receptor signal selectively directed to the myofilaments together with a reduced phosphodiesterase activity associated with the myofibrils. Mechanistically, the enhanced PKA activity on the myofilaments is associated with downregulation of caveolin-3 in the hypertrophic failing rabbit myocytes. Reintroduction of caveolin-3 in the failing myocytes is able to normalize the distribution of β2 adrenergic receptor signal by preventing PKA signal access to the myofilaments and to restore contractile response to adrenergic stimulation.
In hypertrophic rabbit myocytes, selectively enhanced β2 adrenergic receptor signaling toward the myofilaments contributes to elevated PKA activity and PKA phosphorylation of myofilament proteins. Reintroduction of caveolin-3 is able to confine β2 adrenergic receptor signaling and restore myocyte contractility in response to β adrenergic stimulation.
Details
- Title: Subtitle
- Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure
- Creators
- Federica Barbagallo - Sapienza University of RomeBing Xu - University of California, DavisGopireddy R Reddy - University of California, DavisToni West - University of California, DavisQingtong Wang - University of California, DavisQin Fu - University of California, DavisMinghui Li - University of California, DavisQian Shi - University of California, DavisKenneth S Ginsburg - University of California, DavisWilliam Ferrier - University of California, DavisAndrea M Isidori - Sapienza University of RomeFabio Naro - Sapienza University of RomeHemal H Patel - University of California, San DiegoJulie Bossuyt - University of California, DavisDonald Bers - University of California, DavisYang K Xiang - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.119(8), pp.931-943
- DOI
- 10.1161/CIRCRESAHA.116.308964
- PMID
- 27576469
- PMCID
- PMC5307331
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Grant note
- R01 HL092097 / NHLBI NIH HHS R01 HL127764 / NHLBI NIH HHS I01 BX001963 / BLRD VA R01 HL112413 / NHLBI NIH HHS R01 HL091071 / NHLBI NIH HHS P01 HL080101 / NHLBI NIH HHS R01 HL030077 / NHLBI NIH HHS R01 HL082846 / NHLBI NIH HHS I01 BX002900 / BLRD VA R01 HL105242 / NHLBI NIH HHS
- Language
- English
- Date published
- 09/30/2016
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359781002771
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