title: Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses.
abstract: PKA phosphorylates multiple molecules involved in calcium (Ca2+) handling in cardiac myocytes and is considered to be the predominant regulator of β-adrenergic receptor-mediated enhancement of cardiac contractility; however, recent identification of exchange protein activated by cAMP (EPAC), which is independently activated by cAMP, has challenged this paradigm. Mice lacking Epac1 (Epac1 KO) exhibited decreased cardiac contractility with reduced phospholamban (PLN) phosphorylation at serine-16, the major PKA-mediated phosphorylation site. In Epac1 KO mice, intracellular Ca2+ storage and the magnitude of Ca2+ movement were decreased; however, PKA expression remained unchanged, and activation of PKA with isoproterenol improved cardiac contractility. In contrast, direct activation of EPAC in cardiomyocytes led to increased PLN phosphorylation at serine-16, which was dependent on PLC and PKCε. Importantly, Epac1 deletion protected the heart from various stresses, while Epac2 deletion was not protective. Compared with WT mice, aortic banding induced a similar degree of cardiac hypertrophy in Epac1 KO; however, lack of Epac1 prevented subsequent cardiac dysfunction as a result of decreased cardiac myocyte apoptosis and fibrosis. Similarly, Epac1 KO animals showed resistance to isoproterenol- and aging-induced cardiomyopathy and attenuation of arrhythmogenic activity. These data support Epac1 as an important regulator of PKA-independent PLN phosphorylation and indicate that Epac1 regulates cardiac responsiveness to various stresses.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.forename: Meihua
authors.initials: M
authors.lastname: Jin
authors.forename: Iyuki
authors.initials: I
authors.lastname: Namekata
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mototani
authors.forename: Huiling
authors.initials: H
authors.lastname: Jin
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ohnuki
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Tsuneoka
authors.forename: Reiko
authors.initials: R
authors.lastname: Kurotani
authors.forename: Kenji
authors.initials: K
authors.lastname: Suita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Shogo
authors.initials: S
authors.lastname: Hamaguchi
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsunematsu
authors.forename: Yunzhe
authors.initials: Y
authors.lastname: Bai
authors.forename: Sayaka
authors.initials: S
authors.lastname: Suzuki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hidaka
authors.forename: Masanari
authors.initials: M
authors.lastname: Umemura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.forename: Fumio
authors.initials: F
authors.lastname: Ishikawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.forename: Satomi
authors.initials: S
authors.lastname: Adachi-Akahane
authors.forename: Hikaru
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D013312:Stress, Physiological; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D020662:Guanine Nucleotide Exchange Factors; D000099211:Phospholamban; C482601:Epac protein, mouse