Membrane proteins involved in potassium shifts during muscle activity and fatigue

Kristensen, Michael; Hansen, Thomas; Juel, Carsten

doi:10.1152/ajpregu.00534.2004

Cited by 49 publications

(63 citation statements)

References 46 publications

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“…12-14) and on biochemical membrane fractionation studies in rat skeletal muscle (1). Indeed a compelling case for Kir channel localization on T-tubules and plasma membrane was made by Wallinga et al (15), who showed by modeling that maintenance of skeletal muscle excitability and excitation-contraction coupling during repetitive action potential firing requires the presence of Kir channels in these sites for clearance of K ϩ and prevention of positive shifts in the resting membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Dassau

Conti

Radeke

et al. 2011

Journal of Biological Chemistry

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Precise trafficking, localization, and activity of inward rectifier potassium Kir2 channels are important for shaping the electrical response of skeletal muscle. However, how coordinated trafficking occurs to target sites remains unclear. Kir2 channels are tetrameric assemblies of Kir2.x subunits. By immunocytochemistry we show that endogenous Kir2.1 and Kir2.2 are localized at the plasma membrane and T-tubules in rodent skeletal muscle. Recently, a new subunit, Kir2.6, present in human skeletal muscle, was identified as a gene in which mutations confer susceptibility to thyrotoxic hypokalemic periodic paralysis. Here we characterize the trafficking and interaction of wild type Kir2.6 with other Kir2.x in COS-1 cells and skeletal muscle in vivo. Immunocytochemical and electrophysiological data demonstrate that Kir2.6 is largely retained in the endoplasmic reticulum, despite high sequence identity with Kir2.2 and conserved endoplasmic reticulum and Golgi trafficking motifs shared with Kir2.1 and Kir2.2. We identify amino acids responsible for the trafficking differences of Kir2.6. Significantly, we show that Kir2.6 subunits can coassemble with Kir2.1 and Kir2.2 in vitro and in vivo. Notably, this interaction limits the surface expression of both Kir2.1 and Kir2.2. We provide evidence that Kir2.6 functions as a dominant negative, in which incorporation of Kir2.6 as a subunit in a Kir2 channel heterotetramer reduces the abundance of Kir2 channels on the plasma membrane.Inward rectifier potassium (Kir2) channels are key skeletal muscle components involved in determination of muscle resting potential, regulation of electrical excitability, repolarization of the action potential, and clearance of K ϩ from the T-tubule 2 system (1-4 Recently, a search for genes involved in thyrotoxic periodic paralysis (TPP) revealed KCNJ18, which encodes a novel subtype of inward rectifier potassium channel subunit, Kir2.6 (22). Kir2.6 is expressed primarily in skeletal muscle and shares Ͼ98% identity with Kir2.2 (22). Mutations in human Kir2.6 confer susceptibility to TPP, and it has been shown that these disease-associated mutations contribute to atypical current signatures and altered cell excitability (22). Expression studies in heterologous cells demonstrate that Kir2.6 subunits are able to form inwardly rectifying channels and that disease-associated mutations include truncated subunits that do not form functional channels, as well as gain-of-function mutations that increase electrical activity because of misregulation by phosphorylation (22).In addition to their electrophysiological properties, ion channels contribute to electrical events by their abundance on the plasma membrane. Targeting ion channels to subcellular sites and the plasma membrane is important for shaping the electrical response of muscle. Surface expression levels and channel activity are crucial for determining muscle excitability. However, trafficking of Kir2.6 to the plasma membrane has not yet been explored. Moreover, the role of wild type Kir2.6 in normal...

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Section: Discussionmentioning

confidence: 99%

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Dassau

Conti

Radeke

et al. 2011

Journal of Biological Chemistry

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“…The large Na ϩ current at the sarcolemma enables fast conduction and increases the likelihood of initiating an AP in each t tubule, where the relatively small tubular Na ϩ current is normally adequate for propagation (253). Most of the resting K ϩ conductance is due to the K ϩ inward rectifier channels (Kir2.1), which are present at higher density in the T system than at the sarcolemma in mammalian muscle (249). The most common potassium channel on the sarcolemma is the ATP-sensitive K ϩ channel (K ATP or Kir6.2) (417); these channels are also found in the T system but at a lower density (331).…”

Section: Types and Distribution Of Ion Channelsmentioning

confidence: 99%

Skeletal Muscle Fatigue: Cellular Mechanisms

Allen¹,

Lamb²,

Westerblad³

2008

Physiological Reviews

1,861

1,876

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Repeated, intense use of muscles leads to a decline in performance known as muscle fatigue. Many muscle properties change during fatigue including the action potential, extracellular and intracellular ions, and many intracellular metabolites. A range of mechanisms have been identified that contribute to the decline of performance. The traditional explanation, accumulation of intracellular lactate and hydrogen ions causing impaired function of the contractile proteins, is probably of limited importance in mammals. Alternative explanations that will be considered are the effects of ionic changes on the action potential, failure of SR Ca2+ release by various mechanisms, and the effects of reactive oxygen species. Many different activities lead to fatigue, and an important challenge is to identify the various mechanisms that contribute under different circumstances. Most of the mechanistic studies of fatigue are on isolated animal tissues, and another major challenge is to use the knowledge generated in these studies to identify the mechanisms of fatigue in intact animals and particularly in human diseases.

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“…Expression of K ϩ -Cl Ϫ cotransporters KCC1, KCC3, and KCC4, as well as Na ϩ -K ϩ -Cl Ϫ cotransporter NKCC1, has been detected in skeletal muscle. [12][13][14][15][16][17] Interaction of K ϩ -Cl Ϫ cotransport with acid-base transport will be discussed later.…”

Section: Effects Of Acid-base Status On Internal K ؉ Distributionmentioning

confidence: 99%

Effects of pH on Potassium

Aronson

Giebisch

2011

Journal of the American Society of Nephrology

184

141

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Membrane proteins involved in potassium shifts during muscle activity and fatigue

Abstract: Kristensen, Michael, Thomas Hansen, and Carsten Juel. Membrane proteins involved in potassium shifts during muscle activity and fatigue.

Cited by 49 publications

References 46 publications

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Kir2.6 Regulates the Surface Expression of Kir2.x Inward Rectifier Potassium Channels

Skeletal Muscle Fatigue: Cellular Mechanisms

Effects of pH on Potassium

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