ATP-sensitive K<sup>+</sup> -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes

Zhou, Ming; Tanaka, Osamu; Sekiguchi, Masaki; He, Huijing; Yasuoka, Yukiko; Itoh, Hidenori; Kawahara, Katsumasa; Abe, Hiroshi

doi:10.1369/jhc.5a6736.2005

Cited by 38 publications

(39 citation statements)

References 30 publications

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“…While Kir6.2 has roles in glucose homeostasis and cardiac ischemic preconditioning (30), Kir6.1 is critical for maintenance of vascular tone (31) and mitochondrial function (32,33). Our data identify an unanticipated mechanism for the posttranslational regulation of specific Kir6 gene products.…”

Section: Discussionmentioning

confidence: 87%

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Kline

Kurata

Hund

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The coordinated sorting of ion channels to specific plasma membrane domains is necessary for excitable cell physiology. KATP channels, assembled from pore-forming (Kir6.x) and regulatory sulfonylurea receptor subunits, are critical electrical transducers of the metabolic state of excitable tissues, including skeletal and smooth muscle, heart, brain, kidney, and pancreas. Here we show that the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells. Kir6.2 lacking this motif displays aberrant channel targeting due to loss of association with the membrane adapter ankyrin-B (AnkB). Moreover, we demonstrate that this Kir6.2 C-terminal AnkB-binding motif (ABM) serves a dual role in KATP channel trafficking and membrane metabolic regulation and dysfunction in these pathways results in human excitable cell disease. Thus, the KATP channel ABM serves as a previously unrecognized bifunctional touch-point for grading KATP channel gating and membrane targeting and may play a fundamental role in controlling excitable cell metabolic regulation.K ATP channels are critical electrical transducers of the metabolic state of excitable tissues including skeletal and smooth muscle, heart, brain, kidney, and pancreas (1). Mechanistically, decreased metabolism opens K ATP channels, resulting in K ϩ efflux, membrane hyperpolarization, and suppression of action potential formation (1). Conversely, increased metabolism closes K ATP channels, resulting in membrane depolarization, stimulation of electrical activity (2), and subsequent triggering of diverse cellular responses, such as release of hormones and neurotransmitters, or muscle contraction.Given such critical roles in the regulation of electrical excitability in many cell types, it is not surprising that K ATP channel dysfunction results in disease. Human mutations in K ATP channel genes are associated with neonatal diabetes and hyperinsulinemia (3), epilepsy (4), and dilated cardiomyopathy (5). However, despite the clear importance of K ATP function for normal vertebrate physiology, little is resolved regarding the mechanisms responsible for K ATP channel membrane targeting and/or membrane organization.Here we identify a critical motif in the Kir6.2 C-terminal domain that is essential for normal Kir6.2 membrane targeting. We demonstrate that the Kir6.2 C-terminal motif interacts with the cytoskeletal adapter ankyrin-B (AnkB) and that Kir6.2 displays aberrant membrane trafficking when the motif is disrupted or in cells lacking ankyrin-B expression. We demonstrate that the Kir6.2 C-terminal motif displays an unexpected secondary role in Kir6.2 membrane function (K ATP channel activity) by altering K ATP channel ATP sensitivity. Finally, we demonstrate that a human neonatal diabetes disease mutation located in the Kir6.2 C-terminal motif results in a complex ␤ cell phenotype, likely due to the dual role of the C-terminal motif in both Kir6.2 targeting and K ATP channel membrane activity. Together, our findings define a pathway for K ATP ch...

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Section: Discussionmentioning

confidence: 87%

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Kline

Kurata

Hund

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…The 54,000 g precipitate was used as the cell membrane fraction, the 105,000 g precipitate as the microsomal fraction, and the supernatant as the cytoplasmic fraction. Those fractions were confi rmed as previously (Zhou et al 2005(Zhou et al , 2007b.…”

Section: Subcellular Fractionationsmentioning

confidence: 99%

Localization of the Sulphonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Renal Tubular Epithelium

Zhou

Tanaka

et al. 2008

Tohoku J. Exp. Med.

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ATP-sensitive K + (K ATP ) channels in the kidney are considered to play roles in regulating membrane potential according to changes in the intracellular ATP concentration. They are composed of two types of subunits; the pore subunits (Kir6.1, Kir6.2), which are members of the inwardly rectifying K + channel family, and the regulatory subunits, the sulphonylurea receptors, which belong to the ATP-binding cassette (ABC) superfamily. The sulphonylurea receptors (SURs) are receptors of sulphonylureas widely used for the treatment of type 2 diabetes mellitus. The SURs are divided into two isoforms, SUR1 and SUR2, the latter was further divided into SUR2A and SUR2B. In the present study, we have investigated the mRNA expression by RT-PCR assay, and protein expression profi les by immunoblotting, immunohistochemistry, and immunoelectron microscopy with anti SUR2A and anti SUR2B antibodies. RT-PCR detected the presence of mRNA transcripts of the SUR2A and SUR2B, while SUR1 mRNA was barely detected. In immunoblotting, SUR2A protein was detected distinctly in the microsomal fraction, weakly in the mitochondrial fraction and at negligible level in the cell membrane fraction. In contrast, the SUR2B protein was detected intensely in the microsomal fraction, with a low level in the mitochondrial fraction and scarcely in the cell membrane fraction. In immunohistochemistry SUR2A and SUR2B proteins were widely distributed in renal tubular epithelial cells, glomerular mesangial cells, and the endothelium and the smooth muscle of blood vessels. In immunoelectron microscopy, the immunoreactivity was localized in the endoplasmic reticulum and mitochondria throughout the epithelial cells for SUR2A, and dominantly in the apical cytoplasm of the cells for SUR2B. In conclusion, the regulatory subunits of the K ATP channel in the rat kidney are SUR2A and SUR2B; they also are candidate regulatory subunits for the mitochondrial K ATP channel.ATP-sensitive K + channel; sulphonylurea receptor; immunohistochemistry; immunoelectron microscopy; kidney.Tohoku

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“…Cardiomyocyte mitochondria contain both Kir6.1 and Kir6.2 (Lacza et al 2003;Singh et al 2003;Zhou et al 2005), although conflicting views exist (Seharaseyon et al 2000;Kuniyasu et al 2003). How do SURs cooperate with these pore-forming subunits in mitochondria?…”

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confidence: 99%

Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart

Zhou

Suzuki

et al. 2007

J Histochem Cytochem.

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(KK) S U M M A R Y To understand the possible functions and subcellular localizations of sulfonylurea receptors (SURs) in cardiac muscle, polyclonal anti-SUR2A and anti-SUR2B antisera were raised. Immunoblots revealed both SUR2A and SUR2B expression in mitochondrial fractions of rat heart and other cellular fractions such as microsomes and cell membranes. Immunostaining detected ubiquitous expression of both SUR2A and SUR2B in rat heart in the atria, ventricles, interatrial and interventricular septa, and smooth muscles and endothelia of the coronary arteries. Electron microscopy revealed SUR2A immunoreactivity in the cell membrane, endoplasmic reticulum (ER), and mitochondria. SUR2B immunoreactivity was mainly localized in the mitochondria as well as in the ER and cell membrane. Thus, SUR2A and SUR2B are not only the regulatory subunits of sarcolemmal K ATP channels but may also function as regulatory subunits in mitochondrial K ATP channels and play important roles in cardioprotection. (J Histochem Cytochem 55:795-804, 2007)

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ATP-sensitive K⁺ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes

Cited by 38 publications

References 30 publications

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Localization of the Sulphonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Renal Tubular Epithelium

Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart

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ATP-sensitive K+ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes

Cited by 38 publications

References 30 publications

Dual role of K ATP channel C-terminal motif in membrane targeting and metabolic regulation

Dual role of K ATP channel C-terminal motif in membrane targeting and metabolic regulation

Localization of the Sulphonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Renal Tubular Epithelium

Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart

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ATP-sensitive K⁺ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation

Dual role of K _ATP channel C-terminal motif in membrane targeting and metabolic regulation