Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents

Schram, Gernot; Pourrier, Marc; Wang, Zhiguo; White, Michel; Nattel, Stanley

doi:10.1016/s0008-6363(03)00366-3

Cited by 105 publications

(100 citation statements)

References 24 publications

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“…Gene knock-out studies in mice showed that Kir2.1 and Kir2.2 contribute to K ϩ currents in heart in a nonadditive manner, suggesting that these subunits can coassemble in vivo (21). In cardiac myocytes, the diversity of channel conductances, Ba 2ϩ block properties, and pH sensitivity also support a model in which channels are composed of homotetrameric and heterotetrameric subunits (33)(34)(35)(36). Our data showing the overlapping distribution of endogenous Kir2.1 and Kir2.2 channels in skeletal muscle T-tubules are consistent with the idea that a fraction of these subunits coassemble in vivo in skeletal muscle (Fig.…”

Section: Discussionmentioning

confidence: 87%

“…Inward rectifier channels are formed by the homotetrameric or heterotetrameric assembly of subunits. Previous reports demonstrate that Kir2.1, Kir2.2, and Kir2.3 subunits can coassemble to form heterotetrameric channels (33)(34)(35)(36). Notably, many Kir2.1 mutants involved with Andersen-Tawil syndrome dominantly suppress inward rectifier current through tetramerization with Kir2.1, Kir2.2, and Kir2.3 (33).…”

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confidence: 99%

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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: 87%

mentioning

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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“…Inward rectifiers of the mammalian heart are homoor heterotetrameric assemblies of K ir 2.1-3 subunits (16,26,31,36,40) with substantial variation between species (4, 42). Further complexity is generated by chamber-related differences in the expression of K ir 2 subunits (11,14,36).…”

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confidence: 99%

Cloning and expression of cardiac K_ir2.1 and K_ir2.2 channels in thermally acclimated rainbow trout

Hassinen

Paajanen²,

Haverinen³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Hassinen M, Paajanen V, Haverinen J, Eronen H, Vornanen M. Cloning and expression of cardiac Kir2.1 and Kir2.2 channels in thermally acclimated rainbow trout. Am J Physiol Regul Integr Comp Physiol 292: R2328-R2339, 2007. First published February 8, 2007 doi:10.1152/ajpregu.00354.2006.-Potassium currents are plastic entities that modify electrical activity of the heart in various physiological conditions including chronic thermal stress. We examined the molecular basis of the inward rectifier K ϩ current (IK1) in rainbow trout acclimated to cold (4°C, CA) and warm (18°C, WA) temperature. Inward rectifier K ϩ channel (Kir)2.1 and Kir2.2 transcripts were expressed in atrium and ventricle of the trout heart, K ir2.1 being the major component in both cardiac chambers. The relative expression of K ir2.2 was, however, higher (P Ͻ 0.05) in atrium than ventricle. The density of ventricular I K1 was ϳ25% larger (P Ͻ 0.05) in WA than CA trout. Furthermore, the I K1 of the WA trout was 10 times more sensitive to Ba 2ϩ (IC50 0.18 Ϯ 0.42 M) than the IK1 of the CA trout (1.17 Ϯ 0.44 M) (P Ͻ 0.05), and opening kinetics of single K ir2 channels was slower in WA than CA trout (P Ͻ 0.05). When expressed in COS-1 cells, the homomeric K ir2.2 channels demonstrated higher Ba 2ϩ sensitivity (2.88 Ϯ 0.42 M) than Kir2.1 channels (24.99 Ϯ 7.40 M) (P Ͻ 0.05). In light of the different Ba 2ϩ sensitivities of rainbow trout (om)Kir2.1 and omKir2.2 channels, it is concluded that warm acclimation increases either number or activity of the omKir2.2 channels in trout ventricular myocytes. The functional changes in I K1 are independent of omKir2 transcript levels, which remained unaltered by thermal acclimation. Collectively, these findings suggest that thermal acclimation modifies functional properties and subunit composition of the trout K ir2 channels, which may be needed for regulation of cardiac excitability at variable temperatures.inward rectifier potassium channels; atrial myocytes; ventricular myocytes; thermal plasticity STRONG INWARD RECTIFIER POTASSIUM (K ir ) channels conduct inward currents at membrane potentials negative to the K ϩ reversal potential but permit only limited K ϩ efflux at more positive voltages (18, 37) based on the voltage-dependent block of the channels by intracellular Mg 2ϩ and polyamines (8,9,17). The small outward current is physiologically important, since it sets resting membrane potential (RMP), controls excitability, and participates in diverse body functions in various organs. In the heart, the inward rectifier current (I K1 ) clamps the RMP close to K ϩ equilibrium potential and contributes to the late phase 3 repolarization of the action potential (AP) and thereby participates in the regulation of AP duration (18).On the basis of sequence homology, inward rectifier K ϩ channels have been classified into seven subfamilies, K ir 1-K ir 7 (5, 18). Inward rectifiers of the mammalian heart are homoor heterotetrameric assemblies of K ir 2.1-3 subunits (16,26,31,36,40) with substantial variation between spe...

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“…Kir2.1-Kir2.4 (Kir2.x) inwardly rectifying potassium subfamily of channel proteins are the molecular correlates of I K1 [3][4][5], with very distinct isoform-specific properties [3,4]. Important differences exist, for example, in the sensitivity of Kir2.x isoforms to phosphorylating agents [4,6], protons [7][8][9] and to barium ions [10]. Given the increasing evidence that Kir2.x subunits form heteromeric channels when heterologously expressed and in native cardiac cells [10][11][12][13], it is conceivable that such a heteromerization process enhances the regulatory potential of I K1. In humans, although Kir2.1, Kir2.2 and Kir2.3 are all expressed in the myocardium, with Kir2.1≫Kir2.2>Kir2.3 [14], much attention has been given to the Kir2.1 isoform since genetic mutations in the KCNJ2 gene that encodes Kir2.1 have been linked to ion channel malfunctions (channelopathies) associated with cardiac rhythm disturbances [12,15,16].…”

Section: Introductionmentioning

confidence: 99%

“…Important differences exist, for example, in the sensitivity of Kir2.x isoforms to phosphorylating agents [4,6], protons [7][8][9] and to barium ions [10]. Given the increasing evidence that Kir2.x subunits form heteromeric channels when heterologously expressed and in native cardiac cells [10][11][12][13], it is conceivable that such a heteromerization process enhances the regulatory potential of I K1. In humans, although Kir2.1, Kir2.2 and Kir2.3 are all expressed in the myocardium, with Kir2.1≫Kir2.2>Kir2.3 [14], much attention has been given to the Kir2.1 isoform since genetic mutations in the KCNJ2 gene that encodes Kir2.1 have been linked to ion channel malfunctions (channelopathies) associated with cardiac rhythm disturbances [12,15,16]. In addition, when Kir2.1 is co-expressed with other isoforms, the rectification profile and extracellular potassium ([K + ] o ) sensitivity of the Kir2.1 isoform were shown to be dominant in the heteromeric Kir2.1/ Kir2.3 complex [17].…”

Section: Introductionmentioning

confidence: 99%

Kir2.3 isoform confers pH sensitivity to heteromeric Kir2.1/Kir2.3 channels in HEK293 cells

et al. 2007

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Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents

Cited by 105 publications

References 24 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

Cloning and expression of cardiac K_ir2.1 and K_ir2.2 channels in thermally acclimated rainbow trout

Kir2.3 isoform confers pH sensitivity to heteromeric Kir2.1/Kir2.3 channels in HEK293 cells

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