Protein kinase A-dependent phosphorylation of ryanodine receptors increases Ca2+ leak in mouse heart

Satoshi Morimoto, Jin O-Uchi, Makoto Kawai, Toshiyuki Hoshina, Yoichiro Kusakari, Kimiaki Komukai, Hiroyuki Sasaki, Kenichi Hongo, Satoshi Kurihara

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


In heart failure, chronic catecholaminergic stimulation increases diastolic Ca2+ leak from ryanodine receptors (RyRs) of sarcoplasmic reticulum (SR), possibly due to the phosphorylation of RyRs through the activation of protein kinase A (PKA) or Ca2+/calmodulin-dependent protein kinase II (CaMKII). In the present study, we attempted to identify which activated kinase is responsible for the enhanced Ca2+ leak caused by β-adrenergic stimulation. Trabeculae obtained from the hearts of adult male C57BL/6J mice were treated with isoproterenol and then permeabilized with saponin. To examine SR functions, Ca2+ in SR was released with caffeine and measured with fluo-3. The Ca2+ leak in isoproterenol-treated preparations was significantly increased when the PKA-dependent phosphorylation of RyR was increased without the involvement of CaMKII-dependent phosphorylation. Both the increase in Ca2+ leak and the phosphorylation of RyR were blocked by a PKA inhibitor. Our results show that β-adrenergic stimulation increases Ca2+ leak from SR through PKA-dependent phosphorylation of RyR.

Original languageEnglish (US)
Pages (from-to)87-92
Number of pages6
JournalBiochemical and Biophysical Research Communications
Issue number1
StatePublished - Dec 4 2009
Externally publishedYes

Bibliographical note

Funding Information:
Source of Funding: This study was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology [ 18590789 to K.K., 19590833 to K.H., and 19500357 S.K.], the Uehara Memorial Foundation [to Y.K. and S.K.], the Takeda Science Foundation [to K.H.], the Vehicle Racing Commemorative Foundation [to K.H. and S.K.], a Japan Heart Foundation Young Investigator’s Research Grant [to J.O.-U.], the Japan Foundation of Cardiovascular Research [to J.O.-U.], the Kato Memorial Bioscience Foundation [to J.O.-U.], and The Jikei University Research Fund [to J.O.-U.].


  • Ca leak
  • Ca/calmodulin-dependent protein kinase II
  • Protein kinase A
  • Ryanodine receptor
  • β-Adrenoceptor stimulation


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