Inhibition of cAMP-dependent protein kinase under conditions occurring in the cardiac dyad during a Ca2+ transient.
The space between the t-tubule invagination and the sarcoplasmic reticulum (SR) membrane, the dyad, in ventricular myocytes has been predicted to experience very high [Ca2+] for short periods of time during a Ca2+ transient. The dyadic space accommodates many protein kinases responsible for the regulation of Ca2+ handling proteins of the cell. We show in vitro that cAMP-dependent protein kinase (PKA) is inhibited by high [Ca2+] through a shift in the ratio of CaATP/MgATP toward CaATP. We further generate a three-dimensional mathematical model of Ca2+ and ATP diffusion within dyad. We use this model to predict the extent to which PKA would be inhibited by an increased CaATP/MgATP ratio during a Ca2+ transient in the dyad in vivo. Our results suggest that under normal physiological conditions a myocyte paced at 1 Hz would experience up to 55% inhibition of PKA within the cardiac dyad, with inhibition averaging 5% throughout the transient, an effect which becomes more pronounced as the myocyte contractile frequency increases (at 7 Hz, PKA inhibition averages 28% across the dyad throughout the duration of a Ca2+ transient).
Jones
Peter P
PP
Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, United Kingdom. pjones@ucalgary.ca
Bazzazi
Hojjat
H
Kargacin
Gary J
GJ
Colyer
John
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D008954:Models, Biological; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology*; D010766:Phosphorylation; D012518:Sarcomeres / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology*
D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium