%0 Journal Article %1 Karp_2005_493 %A Viatchenko-Karpinski, Serge %A Terentyev, Dmitry %A Jenkins, Leigh Ann %A Lutherer, Lorenz O %A Gy�rke, Sandor %D 2005 %J J. Physiol. %K 15975978 Allosteric Animals, Binding Biological, Calcium Calcium, Cardiac Cardiac, Cardiomyopathies, Cell Cells, Channel Channel, Channels, Chronic Comparative Cultured, Disease, Dogs, Dose-Response Drug, Exchanger, Extramural, Gating, Gov't, Heart, Ion L-Type, Low, Male, Membrane, Models, Muscle Mutant Myocardium, Myocytes, N.I.H., Non-U.S. Output, P.H.S., Proteins, Rats, Receptor Regulation, Relationship, Release Research Reticulum, Ryanodine Sarcoplasmic Signaling, Sites, Sodium-Calcium Sprague-Dawley, Study, Support, Theor, U.S. etical, %N Pt 2 %P 493--504 %R 10.1113/jphysiol.2005.091280 %T Synergistic interactions between Ca$^2+$ entries through L-type Ca$^2+$ channels and Na$^+$-Ca$^2+$ exchanger in normal and failing rat heart. %U http://dx.doi.org/10.1113/jphysiol.2005.091280 %V 567 %X We used confocal Ca$^2+$ imaging and the patch-clamp technique to investigate the interplay between Ca$^2+$ entries through L-type Ca$^2+$ channels (LCCs) and reverse-mode Na$^+$-Ca$^2+$ exchange (NCX) in activating Ca$^2+$-induced Ca$^2+$ release (CICR) from the sarcoplasmic reticulum (SR) in cardiac myocytes from normal and failing rat hearts. In normal myocytes exposed to N(6),2'-O-dibutyryl adenosine-3',5'-cyclic monophosphate (db-cAMP, membrane-permeable form of cAMP), the bell-shaped voltage dependence of cytosolic Ca$^2+$ transients was dramatically broadened due to activation of SR Ca$^2+$ release at high membrane potentials (30-120 mV). This broadening of Ca$^2+$-transient voltage dependence could be prevented by KB-R7943, an inhibitor of the reverse-mode NCX. Trans-sarcolemmal Ca$^2+$ entries were measured fluorometrically in myocytes during depolarizing steps to high membrane potentials. The total Ca$^2+$ entry (deltaF(Tot)) was separated into two Ca$^2+$ entry components, LCC-mediated (deltaF(LCC)) and NCX-mediated (deltaF(NCX)), by exposing the cells to the specific inhibitors of LCCs and reverse-mode NCX, nifedipine and KB-R7943, respectively. In the absence of protein kinase A (PKA) stimulation the amplitude of the Ca$^2+$-inflow signal (deltaF(Tot)) corresponded to the arithmetic sum of the amplitudes of the KB-R7943- and nifedipine-resistant components (deltaF(Tot)=deltaF(LCC)+deltaF(NCX)). PKA activation resulted in significant increases in deltaF(Tot) and deltaF(LCC). Paradoxically, deltaF(Tot) became approximately threefold larger than the sum of the deltaF(NCX) and deltaF(LCC) components. In myocytes from failing hearts, stimulation of PKA failed to induce a shift in Ca$^2+$ release voltage dependence toward more positive membrane potentials. Although the total and NCX-mediated Ca$^2+$ entries were increased again, deltaF(Tot) did not significantly exceed the sum of deltaF(LCC) and deltaF(NCX). We conclude that the LCC and NCX Ca$^2+$-entry pathways interact synergistically to trigger SR Ca$^2+$ release on depolarization to positive membrane potentials in PKA-stimulated cardiac muscle. In heart failure, this new form of Ca$^2+$ release is diminished and may potentially account for the compromised contractile performance and reduced functional reserve in failing hearts.

@article{Karp_2005_493, abstract = {We used confocal {C}a$^{2+}$ imaging and the patch-clamp technique to investigate the interplay between {C}a$^{2+}$ entries through L-type {C}a$^{2+}$ channels (LCCs) and reverse-mode {N}a$^{+}$-{C}a$^{2+}$ exchange (NCX) in activating {C}a$^{2+}$-induced {C}a$^{2+}$ release (CICR) from the sarcoplasmic reticulum (SR) in cardiac myocytes from normal and failing rat hearts. In normal myocytes exposed to N(6),2'-O-dibutyryl adenosine-3',5'-cyclic monophosphate (db-cAMP, membrane-permeable form of cAMP), the bell-shaped voltage dependence of cytosolic {C}a$^{2+}$ transients was dramatically broadened due to activation of SR {C}a$^{2+}$ release at high membrane potentials (30-120 mV). This broadening of {C}a$^{2+}$-transient voltage dependence could be prevented by KB-R7943, an inhibitor of the reverse-mode NCX. Trans-sarcolemmal {C}a$^{2+}$ entries were measured fluorometrically in myocytes during depolarizing steps to high membrane potentials. The total {C}a$^{2+}$ entry (deltaF(Tot)) was separated into two {C}a$^{2+}$ entry components, LCC-mediated (deltaF(LCC)) and NCX-mediated (deltaF(NCX)), by exposing the cells to the specific inhibitors of LCCs and reverse-mode NCX, nifedipine and KB-R7943, respectively. In the absence of protein kinase A (PKA) stimulation the amplitude of the {C}a$^{2+}$-inflow signal (deltaF(Tot)) corresponded to the arithmetic sum of the amplitudes of the KB-R7943- and nifedipine-resistant components (deltaF(Tot)=deltaF(LCC)+deltaF(NCX)). PKA activation resulted in significant increases in deltaF(Tot) and deltaF(LCC). Paradoxically, deltaF(Tot) became approximately threefold larger than the sum of the deltaF(NCX) and deltaF(LCC) components. In myocytes from failing hearts, stimulation of PKA failed to induce a shift in {C}a$^{2+}$ release voltage dependence toward more positive membrane potentials. Although the total and NCX-mediated {C}a$^{2+}$ entries were increased again, deltaF(Tot) did not significantly exceed the sum of deltaF(LCC) and deltaF(NCX). We conclude that the LCC and NCX {C}a$^{2+}$-entry pathways interact synergistically to trigger SR {C}a$^{2+}$ release on depolarization to positive membrane potentials in PKA-stimulated cardiac muscle. In heart failure, this new form of {C}a$^{2+}$ release is diminished and may potentially account for the compromised contractile performance and reduced functional reserve in failing hearts.}, added-at = {2009-06-03T11:20:58.000+0200}, author = {Viatchenko-Karpinski, Serge and Terentyev, Dmitry and Jenkins, Leigh Ann and Lutherer, Lorenz O and Gy�rke, Sandor}, biburl = {https://www.bibsonomy.org/bibtex/25d82557a7ed51c27e4c374c68a31aa00/hake}, description = {The whole bibliography file I use.}, doi = {10.1113/jphysiol.2005.091280}, file = {Karp_2005_493.pdf:Karp_2005_493.pdf:PDF}, interhash = {9ed595866c7f9d02312b9e66f32565e7}, intrahash = {5d82557a7ed51c27e4c374c68a31aa00}, journal = {J. Physiol.}, key = 269, keywords = {15975978 Allosteric Animals, Binding Biological, Calcium Calcium, Cardiac Cardiac, Cardiomyopathies, Cell Cells, Channel Channel, Channels, Chronic Comparative Cultured, Disease, Dogs, Dose-Response Drug, Exchanger, Extramural, Gating, Gov't, Heart, Ion L-Type, Low, Male, Membrane, Models, Muscle Mutant Myocardium, Myocytes, N.I.H., Non-U.S. Output, P.H.S., Proteins, Rats, Receptor Regulation, Relationship, Release Research Reticulum, Ryanodine Sarcoplasmic Signaling, Sites, Sodium-Calcium Sprague-Dawley, Study, Support, Theor, U.S. etical,}, month = Sep, number = {Pt 2}, pages = {493--504}, pii = {jphysiol.2005.091280}, pmid = {15975978}, timestamp = {2009-06-03T11:21:35.000+0200}, title = {Synergistic interactions between {C}a$^{2+}$ entries through L-type {C}a$^{2+}$ channels and {N}a$^{+}$-{C}a$^{2+}$ exchanger in normal and failing rat heart.}, url = {http://dx.doi.org/10.1113/jphysiol.2005.091280}, volume = 567, year = 2005 }