AMP‐activated protein kinase mediates preconditioning in cardiomyocytes by regulating activity and trafficking of sarcolemmal ATP‐sensitive K⁺ channels

Abstract

Brief periods of ischemia and reperfusion that precede sustained ischemia lead to a reduction in myocardial infarct size. This phenomenon, known as ischemic preconditioning, is mediated by signaling pathway(s) that is complex and yet to be fully defined. AMP-activated kinase (AMPK) is activated in cells under conditions associated with ATP depletion and increased AMP/ATP ratio. In the present study, we have taken advantage of a cardiac phenotype overexpressing a dominant negative form of the a2 subunit of AMPK to analyze the role, if any, that AMPK plays in preconditioning the heart. We have found that myocardial preconditioning activates AMPK in wild type, but not transgenic mice. Cardiac cells from transgenic mice could not be preconditioned, as opposed to cells from the wild type. The cytoprotective effect of AMPK was not related to the effect that preconditioning has on mitochondrial membrane potential as revealed by JC-1, a mitochondrial membrane potential-sensitive dye, and laser confocal microscopy. In contrast, experiments with di-8-ANEPPS, a sarcolemmal-potential sensitive dye, has demonstrated that intact AMPK activity is required for preconditioning-induced shortening of the action membrane potential. The preconditioning-induced activation of sarcolemmal K ATP channels was observed in wild type, but not in transgenic mice. HMR 1098, a selective inhibitor of sarcolemmal K ATP channels opening, inhibited preconditioning-induced shortening of action membrane potential as well as cardioprotection afforded by AMPK. Immunoprecipitation followed by Western blotting has shown that AMPK is essential for preconditioninginduced recruitment of sarcolemmal K ATP channels. Based on the obtained results, we conclude that AMPK mediates preconditioning in cardiac cells by regulating the activity and recruitment of sarcolemmal K ATP channels without being a part of signaling pathway that regulates mitochondrial membrane potential.

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

“…In particular, changes in sodium-and calcium-activated potassium channels or in Ca 2+ homeostasis, which have also been suggested to contribute to myotonia in DM1 (55)(56)(57)(58)(59)(60), may mediate some of the observed effect. Consistently, AMPK has been shown to modulate chloride and potassium channels in several cell types, including cardiomyocytes (61,62). Such mechanisms may also contribute to the beneficial effect of rapamycin, as it occurs in the absence of splicing changes.…”

Urocortin 2 autocrine/paracrine and pharmacologic effects to activate AMP-activated protein kinase in the heart

“…Interestingly, AMPK is also activated during ischemic preconditioning (40,41), the physiologic phenomenon by which preceding short durations of ischemia decrease the susceptibility to necrosis during more prolonged and potentially injurious ischemia. AMPK is also activated by other treatment regimens that prevent ischemic injury, such as heat shock (10), adrenergic stimulation (42), and nitric oxide (43).…”

Regulation of Glucose Transporter 3 Surface Expression by the AMP-Activated Protein Kinase Mediates Tolerance to Glutamate Excitation in Neurons

“…Culmsee and et al showed that the transient activation of AMPK with low concentrations of AICAR (0.1 mM) protected hippocampal neurons during glucose deprivation, metabolic, excitotoxic, and oxidative stress (Culmsee et al, 2001). As the induction of AMPK activity has been linked to the preconditioning of cells against energetic stress (Peralta et al, 2001;Sukhodub et al, 2007), Culmsee et al may have inadvertently preconditioned their neurons before stimulation by transiently increasing AMPK activity. In a separate study, McCullough et al (McCullough et al, 2005) identified that the prolonged exposure of neurons to AICAR and the continuous activation of AMPK increased neuronal injury during ischemia (see also Fig.…”