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 due to an enhanced β2 adrenergic receptor (β2AR) 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 β2AR signal by preventing PKA signal access to the myofilaments, and to restore contractile response to adrenergic stimulation.
In hypertrophic rabbit myocytes, selectively enhanced β2AR signaling toward the myofilaments contributes to elevated PKA activity and PKA phosphorylation of myofilament proteins. Reintroduction of caveolin-3 is able to confine β2AR signaling and restore myocyte contractility in response to β-adrenergic stimulation.
Pharmacology, Toxicology and Pharmaceutical Science
2
6%
Engineering
2
6%
Other
3
9%
Unknown
12
35%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 December 2016.
All research outputs
#16,721,208
of 25,373,627 outputs
Outputs from Circulation Research
#6,380
of 7,667 outputs
Outputs of similar age
#218,266
of 348,145 outputs
Outputs of similar age from Circulation Research
#63
of 102 outputs
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