Modulation of sarcoplasmic reticulum Ca2+ release by glycolysis in cat atrial myocytes
In cardiac myocytes, glycolysis and excitationâcontraction (EâC) coupling are functionally coupled. We studied the effects of inhibitors (2-deoxy- d -glucose (2-DG), iodoacetate (IAA)), intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), fructose-1,6-bisphosphate (FBP), phospho...
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Published in | The Journal of physiology Vol. 564; no. 3; pp. 697 - 714 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
9600 Garsington Road , Oxford , OX4 2DQ , UK
The Physiological Society
01.05.2005
Blackwell Science Ltd Blackwell Science Inc |
Subjects | |
Online Access | Get full text |
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Summary: | In cardiac myocytes, glycolysis and excitationâcontraction (EâC) coupling are functionally coupled. We studied the effects
of inhibitors (2-deoxy- d -glucose (2-DG), iodoacetate (IAA)), intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), fructose-1,6-bisphosphate
(FBP), phosphoenolpyruvate (PEP)) and products (pyruvate, l -lactate) of glycolysis on sarcoplasmic reticulum (SR) Ca 2+ release and uptake in intact and permeabilized cat atrial myocytes. In field-stimulated (0.5â0.7 Hz) intact myocytes, 2-DG
(10 m m ) and IAA (1 m m ) caused elevation of diastolic [Ca 2+ ] i and [Ca 2+ ] i transient alternans (Ca 2+ alternans) followed by a decrease of the amplitude of the [Ca 2+ ] i transient. Focal application of 2-DG resulted in local Ca 2+ alternans that was confined to the region of exposure. 2-DG and IAA slowed the decay kinetics of the [Ca 2+ ] i transient and delayed its recovery (positive staircase) after complete SR depletion, suggesting impaired activity of the
SR Ca 2+ -ATPase (SERCA). 2-DG and IAA reduced the rate of reuptake of Ca 2+ into the SR which was accompanied by a 15â20% decrease of SR Ca 2+ load. Major changes of mitochondrial redox state (measured as FAD autofluorescence) were not observed after inhibition of
glycolysis. Pyruvate (10 m m ) and l -lactate (10 m m ) elicited similar changes of the [Ca 2+ ] i transient. Pyruvate, l -lactate and IAA â but not 2-DG â induced intracellular acidosis. Recording of single channel activity of ryanodine receptors
(RyRs) incorporated into lipid bilayers revealed complex modulation by glycolytic intermediates and products (1 m m each): some were without effect (G6P, PEP, l -lactate) while others either increased (F6P, +40%; FBP, +265%) or decreased (pyruvate, â58%) the open probability of the
RyR. Consistent with these findings, spontaneous SR Ca 2+ release (Ca 2+ sparks) in permeabilized myocytes was facilitated by FBP and inhibited by pyruvate. The results indicate that in atrial myocytes
glycolysis regulates Ca 2+ release from the SR by multiple mechanisms including direct modulation of RyR activity by intermediates and products of glycolysis
and modulation of SERCA activity through local changes of glycolytically derived ATP. |
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Bibliography: | J. Kockskämper and A. V. Zima contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 J. Kockskämper: Abteilung Kardiologie und Pneumologie Georg-August-Universität, Robert-Koch-Str. 40, 37075 Gättingen, Germany. |
ISSN: | 0022-3751 1469-7793 |
DOI: | 10.1113/jphysiol.2004.078782 |