Inhibition of Sarcolemmal Na
            <sup>+</sup>
            ,K
            <sup>+</sup>
            -ATPase Activity Reduces the Infarct Size–Limiting Effect of Preconditioning in Rabbit Hearts

Nawada, Ryuzo; Murakami, Tomoyuki; Iwase, Tomoyuki; Nagai, Kazuyuki; Morita, Yasuhiro; Kouchi, Ichiro; Akao, Masaharu; Sasayama, Shígetake

doi:10.1161/01.cir.96.2.599

Cited by 31 publications

(18 citation statements)

References 25 publications

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“…Numerous studies have demonstrated a role for Na/KATPase in the heart's response to ischemia reperfusion (39). Notably, a functional link between Na/K-ATPase and K ATP has also been described (27).…”

Section: Discussionmentioning

confidence: 99%

Ankyrin-B Regulates Kir6.2 Membrane Expression and Function in Heart

Kline

Hund

et al. 2010

Journal of Biological Chemistry

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Ankyrin polypeptides are critical for normal membrane protein expression in diverse cell types, including neurons, myocytes, epithelia, and erythrocytes. Ankyrin dysfunction results in defects in membrane expression of ankyrin-binding partners (including ion channels, transporters, and cell adhesion molecules), resulting in aberrant cellular function and disease. Here, we identify a new role for ankyrin-B in cardiac cell biology. We demonstrate that cardiac sarcolemmal K ATP channels directly associate with ankyrin-B in heart via the K ATP channel ␣-subunit Kir6.2. We demonstrate that primary myocytes lacking ankyrin-B display defects in Kir6.2 protein expression, membrane expression, and function. Moreover, we demonstrate a secondary role for ankyrin-B in regulating K ATP channel gating. Finally, we demonstrate that ankyrin-B forms a membrane complex with K ATP channels and the cardiac Na/K-ATPase, a second key membrane transporter involved in the cardiac ischemia response. Collectively, our new findings define a new role for cardiac ankyrin polypeptides in regulation of ion channel membrane expression in heart.Ankyrins are multivalent adapter proteins required for the proper membrane expression of ion channels, transporters, cell adhesion molecules, and structural and signaling molecules in excitable and non-excitable cells (1). Three genes (ANK1, ANK2, and ANK3) encode a host of structurally similar but functionally distinct ankyrin polypeptides (ankyrin-R, ankyrin-B, and ankyrin-G, respectively) with specific roles in erythrocyte membrane structure, cardiac excitability, polarized epithelial ion regulation, and neuronal development. In heart, ankyrins regulate membrane excitability by coordinating the expression of voltagegated Na ϩ and Ca 2ϩ channels, cytoskeletal elements, key membrane transporters and pumps, and signaling proteins (2, 3). The importance of cardiac ankyrins for normal physiology is demonstrated by human disease associated with dysfunction in ankyrinbased pathways. For example, dysfunction in the ankyrin-G-based cellular pathway for voltage-gated Na ϩ channel membrane expression is associated with the potentially fatal Brugada syndrome cardiac arrhythmia due to reduced membrane sodium current (4, 5).In heart, ankyrin-B is critical for regulating membrane protein expression, with ankyrin-B dysfunction linked to cardiovascular disease in humans and mice (6 -10). Humans harboring ANK2 loss-of-function gene variants display a complex cardiac phenotype that may include sinus node disease, conduction defects, ventricular arrhythmia, and sudden death (6 -8, 10). Mice lacking one functional allele of Ank2 (ankyrin-B ϩ/Ϫ mice) display similar phenotypes and have been utilized to identify and validate potential ankyrin-B protein partners that contribute to the human disease phenotype (6). More recently, ANK2 variants have been linked with arrhythmia susceptibility in the general human population (11). Furthermore, ankyrin-B dysfunction has been identified following myocardial infarction (12, 13), sug...

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Section: Discussionmentioning

confidence: 99%

Ankyrin-B Regulates Kir6.2 Membrane Expression and Function in Heart

Kline

Hund

et al. 2010

Journal of Biological Chemistry

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“…32,33 Inhibition of Na ϩ /K ϩ -ATPase reduced the infarct size-limiting effect by IPC, 14 suggesting the important role of the ATPase. Functional interaction between the sarcolemmal K ATP channel and Na ϩ /K ϩ -ATPase has been reported.…”

Section: Contribution Of Namentioning

confidence: 99%

“…Furthermore, it has been demonstrated that the inhibition of Na ϩ /K ϩ -ATPase also abolished the infarct size-limiting effect induced by IPC. 14 Although these candidates are considered to modify intracellular Na ϩ kinetics that is critically coupled with the subsequent Ca 2ϩ overload, the details of the change in Na ϩ kinetics are not clear.…”

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confidence: 99%

Role of Intracellular Na ⁺ Kinetics in Preconditioned Rat Heart

Imahashi

Yoshioka

Kusuoka

2001

Circulation Research

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“…IPC limits the inhibition of sarcolemmal Na + -K + ATPase activity in the acute phase of ischemia and increases Na + -Ca + exchange activity [22]. Haruna et al [23] recently reported that the infarct limiting effect of IPC may be modulated via an interaction between Na + -K + ATPase and sarcK ATP channels.…”

Section: Sarck Atp As a Distal Effectormentioning

confidence: 99%

Sarcolemmal and mitochondrial K_ATP channels and myocardial ischemic preconditioning

Peart

Gross

2002

J Cellular Molecular Medi

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Ischemic preconditioning (IPC) is the phenomenon whereby brief periods of ischemia have been shown to protect the myocardium against a sustained ischemic insult. The result of IPC may be manifest as a marked reduction in infarct size, myocardial stunning, or incidence of arrhythmias. While many substances and pathways have been proposed to play a role in the signal transduction mediating the cardioprotective effect of IPC, overwhelming evidence indicates an intimate involvement of the ATP-sensitive potassium channel (K ATP channel) in this process. Initial hypotheses suggested that the surface or sarcolemmal K ATP (sarcK ATP ) channel mediated the cardioprotective effects of IPC. However, much research has subsequently supported a major role for the mitochondrial K ATP channel (mitoK ATP ) as the one involved in IPC-mediated cardioprotection. This review presents evidence to support a role for the sarcK ATP or the mitoK ATP channel as either triggers and/or downstream mediators in the phenomenon of IPC.

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Inhibition of Sarcolemmal Na ⁺ ,K ⁺ -ATPase Activity Reduces the Infarct Size–Limiting Effect of Preconditioning in Rabbit Hearts

Cited by 31 publications

References 25 publications

Ankyrin-B Regulates Kir6.2 Membrane Expression and Function in Heart

Ankyrin-B Regulates Kir6.2 Membrane Expression and Function in Heart

Role of Intracellular Na ⁺ Kinetics in Preconditioned Rat Heart

Sarcolemmal and mitochondrial K_ATP channels and myocardial ischemic preconditioning

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Inhibition of Sarcolemmal Na + ,K + -ATPase Activity Reduces the Infarct Size–Limiting Effect of Preconditioning in Rabbit Hearts

Cited by 31 publications

References 25 publications

Ankyrin-B Regulates Kir6.2 Membrane Expression and Function in Heart

Ankyrin-B Regulates Kir6.2 Membrane Expression and Function in Heart

Role of Intracellular Na + Kinetics in Preconditioned Rat Heart

Sarcolemmal and mitochondrial KATP channels and myocardial ischemic preconditioning

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Product

Resources

About

Inhibition of Sarcolemmal Na ⁺ ,K ⁺ -ATPase Activity Reduces the Infarct Size–Limiting Effect of Preconditioning in Rabbit Hearts

Role of Intracellular Na ⁺ Kinetics in Preconditioned Rat Heart

Sarcolemmal and mitochondrial K_ATP channels and myocardial ischemic preconditioning