[Show abstract][Hide abstract] ABSTRACT: The cardiovascular system operates under demands ranging from conditions of rest to extreme stress. One mechanism of cardiac stress tolerance is action potential duration shortening driven by ATP-sensitive potassium (K(ATP)) channels. K(ATP) channel expression has a significant physiologic impact on action potential duration shortening and myocardial energy consumption in response to physiologic heart rate acceleration. However, the effect of reduced channel expression on action potential duration shortening in response to severe metabolic stress is yet to be established. Here, transgenic mice with myocardium-specific expression of a dominant negative K(ATP) channel subunit were compared with littermate controls. Evaluation of K(ATP) channel whole cell current and channel number/patch was assessed by patch clamp in isolated ventricular cardiomyocytes. Monophasic action potentials were monitored in retrogradely perfused, isolated hearts during the transition to hypoxic perfusate. An 80-85% reduction in cardiac K(ATP) channel current density results in a similar magnitude, but significantly slower rate, of shortening of the ventricular action potential duration in response to severe hypoxia, despite no significant difference in coronary flow. Therefore, the number of functional cardiac sarcolemmal K(ATP) channels is a critical determinant of the rate of adaptation of myocardial membrane excitability, with implications for optimization of cardiac energy consumption and consequent cardioprotection under conditions of severe metabolic stress.
Biochemical and Biophysical Research Communications 11/2011; 415(4):637-41. DOI:10.1016/j.bbrc.2011.10.125 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The gene encoding T cell immunoglobulin and mucin domain-1 (Tim-1) is linked to atopy and asthma susceptibility in mice and humans. Tim-1 is a transmembrane protein expressed on activated lymphocytes and appears to have a role as a co-stimulatory receptor in T cells. The protein has not been shown to have enzymatic activity but contains a site within its cytoplasmic tail predicted to be a target for tyrosine kinases. Here, we show that Tim-1 can associate with the kinase Fyn, a member of the Src family of tyrosine kinases. This association does not require Fyn's kinase activity and is independent of the phosphorylation of a conserved tyrosine present within the cytoplasmic tail of Tim-1. Fyn is necessary for phosphorylation of this tyrosine in Tim-1 and the phosphorylation of Tim-1 varies with the levels of Fyn present in cells. These data suggest a role for Fyn in the signaling downstream of Tim-1.
[Show abstract][Hide abstract] 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 (K(ATP)) 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 K(ATP) 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 K(ATP) 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 K(ATP) 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 K(ATP) 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.
Journal of Molecular and Cellular Cardiology 03/2011; 51(1):72-81. DOI:10.1016/j.yjmcc.2011.03.010 · 4.66 Impact Factor