Exercise-induced expression of cardiac ATP-sensitive potassium channels promotes action potential shortening and energy conservation

Abstract

Physical activity is one of the most important determinants of cardiac function. The ability of the heart to increase delivery of oxygen and metabolic fuels relies on an array of adaptive responses necessary to match bodily demand while avoiding exhaustion of cardiac resources. The ATP-sensitive potassium (KATP) channel has the unique ability to adjust cardiac membrane excitability in accordance with ATP and ADP levels, and up-regulation of its expression that occurs in response to exercise could represent a critical element of this adaption. However, the mechanism by which KATP channel expression changes result in a beneficial effect on cardiac excitability and function remains to be established. Here, we demonstrate that an exercise-induced rise in KATP channel expression enhanced the rate and magnitude of action potential shortening in response to heart rate acceleration. This adaptation in membrane excitability promoted significant reduction in cardiac energy consumption under escalating workloads. Genetic disruption of normal KATP channel pore function abolished the exercise-related changes in action potential duration adjustment and caused increased cardiac energy consumption. Thus, an expression-driven enhancement in the KATP channel-dependent membrane response to alterations in cardiac workload represents a previously unrecognized mechanism for adaptation to physical activity and a potential target for cardioprotection.

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

“…Cardiomyocyte Isolation-Single ventricular cardiomyocytes from anesthetized (Avertin, 2.5% solution of tribromoethanol in 2-methyl-2-butanol, Sigma, 240 mg/kg intraperitoneally) male, heterozygous AC3-I and AC3-C transgenic mice (32) and their wild-type littermates aged 10 -12 weeks were enzymatically isolated (24). Hearts were cannulated in situ then rapidly excised and retrogradely perfused at 90 mm Hg at 37°C, pH 7.4, for 5 min with Hepes buffer (Medium 199, Sigma), 1 min with a "low calcium" medium (100 mmol/liter NaCl, 10 mmol/liter KCl, 1.2 mmol/liter KH 2 PO 4 , 5 mmol/liter MgSO 4 , 20 mmol/ liter glucose, 50 mmol/liter taurine, 10 mmol/liter HEPES supplemented with 0.13 mmol/liter CaCl 2 , 2.1 mmol/liter EGTA), then 13 min with low calcium medium supplemented with 1% bovine serum albumin, 0.2 mmol/liter CaCl 2 , collagenase (type IV, 22 units/ml, Worthington) and Pronase (100 g/ml, Serva).…”

“…Western Blot-Whole cell protein extracts (24) were used for immunoblotting with CaMKII (pan), phospho-CaMKII (Thr-286, Cell Signaling), and anti-GAPDH (Santa Cruz Biotechnologies) antibodies.…”

“…sumption in the compartmentalized cellular environment (17,22) allows K ATP channel opening to be regulated not only by severe metabolic stress, such as during ischemia, but also by heart rate acceleration within the range induced by normal physical activity (23,24). When activated by a reduced ATP/ ADP ratio, reflecting either increased cellular metabolic demand or reduced cellular ATP generation, K ATP channel-dependent potassium efflux shortens cardiac action potential duration, allowing for a longer diastolic interval that supports myocardial relaxation and restoration of ion gradients and energetic resources as well as limits sodium and calcium entry into the cell and thus reduces energy requirements for ion transport/exchange and contraction (1,9,10,(23)(24)(25)(26)(27)(28).…”

“…When activated by a reduced ATP/ ADP ratio, reflecting either increased cellular metabolic demand or reduced cellular ATP generation, K ATP channel-dependent potassium efflux shortens cardiac action potential duration, allowing for a longer diastolic interval that supports myocardial relaxation and restoration of ion gradients and energetic resources as well as limits sodium and calcium entry into the cell and thus reduces energy requirements for ion transport/exchange and contraction (1,9,10,(23)(24)(25)(26)(27)(28).…”

“…For instance, in the heart an increase in functional sarcolemmal K ATP channel presence enhances the speed and degree of shortening of action potentials and limits cardiac energy consumption in response to escalating workloads, whereas a decrease in their presence has the opposite effect (24). Additionally, although even a small fraction of the normal population of K ATP channels can dramatically shorten the action potential duration in response to severe metabolic stress, the speed at which this myocardially protective action occurs is K ATP channel expression-dependent (25).…”