%0 Journal Article %1 Song_2008_31531 %A Song, Qiujing %A Saucerman, Jeffrey J %A Bossuyt, Julie %A Bers, Donald M %D 2008 %J J Biol Chem %K Acid Aging, Amino Animals; Binding; Biological; Biosensing Calcium Calcium, Calmodulin, Calmodulin-Binding Cardiac, Cell Cells, Cultured; Data; Energy Fluorescence Humans; Models, Molecular Myocytes, Protein Proteins, Rabbits; Resonance Sequence Sequence; Signaling; Specificity Substrate Survival; Techniques; Transfer; chemistry/genetics/metabolism; cytology/metabolism; metabolism; physiology; %N 46 %P 31531--31540 %R 10.1074/jbc.M804902200 %T Differential integration of Ca2+-calmodulin signal in intact ventricular myocytes at low and high affinity Ca2+-calmodulin targets. %U http://dx.doi.org/10.1074/jbc.M804902200 %V 283 %X Cardiac myocyte intracellular calcium varies beat-to-beat and calmodulin (CaM) transduces Ca2+ signals to regulate many cellular processes (e.g. via CaM targets such as CaM-dependent kinase and calcineurin). However, little is known about the dynamics of how CaM targets process the Ca2+ signals to generate appropriate biological responses in the heart. We hypothesized that the different affinities of CaM targets for the Ca2+-bound CaM (Ca2+-CaM) shape their actions through dynamic and tonic interactions in response to the repetitive Ca2+ signals in myocytes. To test our hypothesis, we used two fluorescence resonance energy transfer-based biosensors, BsCaM-45 (Kd = approximately 45 nm) and BsCaM-2 (Kd = approximately 2 nm), to monitor the real time Ca2+-CaM dynamics at low and high affinity CaM targets in paced adult ventricular myocytes. Compared with BsCaM-2, BsCaM-45 tracks the beat-to-beat Ca2+-CaM alterations more closely following the Ca2+ oscillations at each myocyte contraction. When pacing frequency is raised from 0.1 to 1.0 Hz, the higher affinity BsCaM-2 demonstrates significant elevation of diastolic Ca2+-CaM binding compared with the lower affinity BsCaM-45. Biochemically detailed computational models of Ca2+-CaM biosensors in beating cardiac myocytes revealed that the different Ca2+-CaM binding affinities of BsCaM-2 and BsCaM-45 are sufficient to predict their differing kinetics and diastolic integration. Thus, data from both experiments and computational modeling suggest that CaM targets with low versus high Ca2+-CaM affinities (like CaM-dependent kinase versus calcineurin) respond differentially to the same Ca2+ signal (phasic versus integrating), presumably tuned appropriately for their respective and distinct Ca2+ signaling pathways.

@article{Song_2008_31531, abstract = {Cardiac myocyte intracellular calcium varies beat-to-beat and calmodulin (CaM) transduces Ca2+ signals to regulate many cellular processes (e.g. via CaM targets such as CaM-dependent kinase and calcineurin). However, little is known about the dynamics of how CaM targets process the Ca2+ signals to generate appropriate biological responses in the heart. We hypothesized that the different affinities of CaM targets for the Ca2+-bound CaM (Ca2+-CaM) shape their actions through dynamic and tonic interactions in response to the repetitive Ca2+ signals in myocytes. To test our hypothesis, we used two fluorescence resonance energy transfer-based biosensors, BsCaM-45 (Kd = approximately 45 nm) and BsCaM-2 (Kd = approximately 2 nm), to monitor the real time Ca2+-CaM dynamics at low and high affinity CaM targets in paced adult ventricular myocytes. Compared with BsCaM-2, BsCaM-45 tracks the beat-to-beat Ca2+-CaM alterations more closely following the Ca2+ oscillations at each myocyte contraction. When pacing frequency is raised from 0.1 to 1.0 Hz, the higher affinity BsCaM-2 demonstrates significant elevation of diastolic Ca2+-CaM binding compared with the lower affinity BsCaM-45. Biochemically detailed computational models of Ca2+-CaM biosensors in beating cardiac myocytes revealed that the different Ca2+-CaM binding affinities of BsCaM-2 and BsCaM-45 are sufficient to predict their differing kinetics and diastolic integration. Thus, data from both experiments and computational modeling suggest that CaM targets with low versus high Ca2+-CaM affinities (like CaM-dependent kinase versus calcineurin) respond differentially to the same Ca2+ signal (phasic versus integrating), presumably tuned appropriately for their respective and distinct Ca2+ signaling pathways.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Song, Qiujing and Saucerman, Jeffrey J and Bossuyt, Julie and Bers, Donald M}, biburl = {https://www.bibsonomy.org/bibtex/24bdd7614bbed14e5f0522ef2c97a87eb/hake}, description = {The whole bibliography file I use.}, doi = {10.1074/jbc.M804902200}, file = {Song_2008_31531.pdf:Song_2008_31531.pdf:PDF}, institution = {Department of Physiology, Loyola University Chicago, Maywood, Illinois 60153, USA.}, interhash = {11a420dce083d50fb73d3a4483bef5c1}, intrahash = {4bdd7614bbed14e5f0522ef2c97a87eb}, journal = {J Biol Chem}, keywords = {Acid Aging, Amino Animals; Binding; Biological; Biosensing Calcium Calcium, Calmodulin, Calmodulin-Binding Cardiac, Cell Cells, Cultured; Data; Energy Fluorescence Humans; Models, Molecular Myocytes, Protein Proteins, Rabbits; Resonance Sequence Sequence; Signaling; Specificity Substrate Survival; Techniques; Transfer; chemistry/genetics/metabolism; cytology/metabolism; metabolism; physiology;}, month = Nov, number = 46, pages = {31531--31540}, pdf = {Song_2008_31531.pdf}, pii = {M804902200}, pmid = {18790737}, timestamp = {2009-06-03T11:21:32.000+0200}, title = {Differential integration of Ca2+-calmodulin signal in intact ventricular myocytes at low and high affinity Ca2+-calmodulin targets.}, url = {http://dx.doi.org/10.1074/jbc.M804902200}, volume = 283, year = 2008 }