PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure.
The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation-contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.
Reiken
Steven
S
Center for Molecular Cardiology, Box 65, Columbia University College of Physicians and Surgeons, Room 9-401, 630 West 168th Street, New York, NY 10032, USA.
Lacampagne
Alain
A
Zhou
Hua
H
Kherani
Aftab
A
Lehnart
Stephan E
SE
Ward
Chris
C
Huang
Fannie
F
Gaburjakova
Marta
M
Gaburjakova
Jana
J
Rosemblit
Nora
N
Warren
Michelle S
MS
He
Kun-Lun
KL
Yi
Geng-Hua
GH
Wang
Jie
J
Burkhoff
Daniel
D
Vassort
Guy
G
Marks
Andrew R
AR
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004285:Dogs; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000235:genetics; D013347:Subcellular Fractions; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism
D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases; D022061:Tacrolimus Binding Protein 1A; D002118:Calcium