Epac2 mediates cardiac β1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia.
BACKGROUND
β-Adrenergic receptor (β-AR) activation can provoke cardiac arrhythmias mediated by cAMP-dependent alterations of Ca(2+) signaling. However, cAMP can activate both protein kinase A and an exchange protein directly activated by cAMP (Epac), but their functional interaction is unclear. In heart, selective Epac activation can induce potentially arrhythmogenic sarcoplasmic reticulum (SR) Ca(2+) release that involves Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) effects on the ryanodine receptor (RyR).


RESULTS
We tested whether physiological β-AR activation causes Epac-mediated SR Ca(2+) leak and arrhythmias and whether it requires Epac1 versus Epac2, β(1)-AR versus β(2)-AR, and CaMKIIδ-dependent phosphorylation of RyR2-S2814. We used knockout (KO) mice for Epac1, Epac2, or both. All KOs exhibited unaltered basal cardiac function, Ca(2+) handling, and hypertrophy in response to pressure overload. However, SR Ca(2+) leak induced by the specific Epac activator 8-CPT in wild-type mice was abolished in Epac2-KO and double-KO mice but was unaltered in Epac1-KO mice. β-AR-induced arrhythmias were also less inducible in Epac2-KO versus wild-type mice. β-AR activation with protein kinase A inhibition mimicked 8-CPT effects on SR Ca(2+) leak and was prevented by blockade of β(1)-AR but not β(2)-AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKIIδ or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT-induced SR Ca(2+) leak.


CONCLUSIONS
β(1)-AR activates Epac2 to induce SR Ca(2+) leak via CaMKIIδ-dependent phosphorylation of RyR2-S2814. This pathway contributes to β-AR-induced arrhythmias and reduced cardiac function.
Department of Pharmacology, University of California Davis, Davis, CA 95616-8636, USA.
Laëtitia
L
Pereira
Hongqiang
H
Cheng
Dieu Hung
DH
Lao
Li
L
Na
Ralph J
RJ
van Oort
Joan Heller
JH
Brown
Xander H T
XH
Wehrens
Ju
J
Chen
Donald M
DM
Bers
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000172:deficiency* / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology
D020662:Guanine Nucleotide Exchange Factors; C486707:Rapgef4 protein, mouse; D018342:Receptors, Adrenergic, beta-1; D002118:Calcium