AKAP complex regulates Ca2+ re-uptake into heart sarcoplasmic reticulum.
The beta-adrenergic receptor/cyclic AMP/protein kinase A (PKA) signalling pathway regulates heart rate and contractility. Here, we identified a supramolecular complex consisting of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2), its negative regulator phospholamban (PLN), the A-kinase anchoring protein AKAP18delta and PKA. We show that AKAP18delta acts as a scaffold that coordinates PKA phosphorylation of PLN and the adrenergic effect on Ca(2+) re-uptake. Inhibition of the compartmentalization of this cAMP signalling complex by specific molecular disruptors interferes with the phosphorylation of PLN. This prevents the subsequent release of PLN from SERCA2, thereby affecting the Ca(2+) re-uptake into the sarcoplasmic reticulum induced by adrenergic stimuli.
Lygren
Birgitte
B
Biotechnology Centre of Oslo, University of Oslo, PO Box 1125, Blindern, N-0317 Oslo, Norway.
Carlson
Cathrine Rein
CR
Santamaria
Katja
K
Lissandron
Valentina
V
McSorley
Theresa
T
Litzenberg
Jessica
J
Lorenz
Dorothea
D
Wiesner
Burkhard
B
Rosenthal
Walter
W
Zaccolo
Manuela
M
Taskén
Kjetil
K
Klussmann
Enno
E
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D000099211:Phospholamban
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D002118:Calcium; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C526078:Akap7 protein, rat; C506948:Atp2a2 protein, rat