Inward Rectifier Potassium Channels (Kir2.x) and Caveolin-3 Domain–Specific Interaction

Vaidyanathan, Ravi; Ert, Hanora Van; Haq, Kazi T.; Morotti, Stefano; Esch, Samuel; McCune, Elise; Grandi, Eleonora; Eckhardt, Lee L.

doi:10.1161/circep.117.005800

Cited by 29 publications

(45 citation statements)

References 60 publications

(80 reference statements)

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“…This review will focus on the importance of this microdomain and how it determines cardiac excitability. Recent publications by us and other groups have reported that the ion channels that regulate cardiac excitability form membrane bound macromolecular complexes ( Milstein et al, 2012 ; Vaidyanathan et al, 2013 , 2018 ). Additionally, we will discuss the downstream effects of Cav3 mutations on cardiac excitability as a cause for ventricular arrhythmias in inherited arrhythmia syndromes.…”

Section: Caveolin and Ion Channel Microdomainsmentioning

confidence: 99%

Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel

2018

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In human cardiac ventricular myocytes, caveolin-3 functions as a scaffolding and regulatory protein for signaling molecules and compartmentalizes ion channels. Our lab has recently explored this sub-cellular microdomain and found that potassium inward rectifier Kir2.x is found in association with caveolin-3. The three cardiac Kir2.x isoforms (Kir2.1, Kir2.2, and Kir2.3) are the molecular correlates of IK1 in the heart, of which Kir2.1 is the dominant isoform in the ventricle. Kir2.1 channels assemble with Kir2.2 and Kir2.3 forming hetero-tetramers that modulate IK1. IK1 sets the resting membrane potential and assists with terminal phase 3 ventricular repolarization. In our studies using native human ventricular tissue, Kir2.x co-localizes with caveolin-3 and significance of the association between Kir2.x and caveolin-3 is emphasized in relation to mutations in the gene which encodes caveolin-3, CAV3, associated with Long QT Syndrome 9 (LQT9). LQT9-associated CAV3 mutations cause decreased current density in Kir2.1 and Kir2.2 as homomeric and heteromeric channels, which affects repolarization and membrane potential stability. A portion of Kir2.1 cardiac localization parallels that of the cardiac sodium channel (Nav1.5). This may have implications for Long QT9 in which CAV3 mutations cause an increase in the late current of Nav1.5 (INa−L) via nNOS mediated nitrosylation of Nav1.5. In iPS-CMs, expression of LQT9 CAV3 mutations resulted in action potential duration (APD) prolongation and early-after depolarizations (EADs), supporting the arrhythmogenicity of LQT9. To evaluate the combined effect of the CAV3 mutants on INa−L and IK1, we studied both ventricular and Purkinje myocyte mathematical modeling. Interestingly, mathematical ventricular myocytes, similar to iPS-CMs, demonstrated EADs but no sustained arrhythmia. In contrast, Purkinje modeling demonstrated delayed-after depolarizations (DADs) driven mechanism for sustained arrhythmia, dependent on the combined loss of IK1 and gain of INa−L. This finding changes the overall assumed arrhythmia phenotype for LQT9. In future studies, we are exploring caveolar micro-domain disruption in heart failure and how this effects Kir2.x and Nav1.5. Here we review the caveolae cardiac microdomain of Kir2.x and Nav1.5 and explore some of the downstream effects of caveolin-3 and caveolae disruption in specific clinical scenarios.

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Section: Caveolin and Ion Channel Microdomainsmentioning

confidence: 99%

Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel

2018

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“…; Vaidyanathan et al . ). Furthermore, Cav3‐F97C was shown to differentially regulate current density and cell surface expression of Kir2.x homomeric and heteromeric channels, which can lead to delayed afterdepolarizations as a possible arrhythmia mechanism (Vaidyanathan et al .…”

Section: Discussionmentioning

confidence: 97%

“…The present study demonstrates that the Cav3-F97C and S141R variants can also cause loss of function effects on K v 4.2 and K v 4.3 channels responsible for I to and gain of function effects on Ca v 1.2 channels increasing I Ca,L as contributors to the disease phenotype. Other studies have suggested that the LQTS9 Cav3 mutations can also cause a decrease in K ir 2.1 current density, which can contribute to the arrhythmia phenotype Vaidyanathan et al 2018). Furthermore, Cav3-F97C was shown to differentially regulate current density and cell J Physiol 597.6 surface expression of Kir2.x homomeric and heteromeric channels, which can lead to delayed afterdepolarizations as a possible arrhythmia mechanism (Vaidyanathan et al 2018).…”

Section: Lqts9 Cav3 Mutations Apd Prolongation and Arrhythmiasmentioning

confidence: 99%

“…Other studies have suggested that the LQTS9 Cav3 mutations can also cause a decrease in K ir 2.1 current density, which can contribute to the arrhythmia phenotype Vaidyanathan et al 2018). Furthermore, Cav3-F97C was shown to differentially regulate current density and cell J Physiol 597.6 surface expression of Kir2.x homomeric and heteromeric channels, which can lead to delayed afterdepolarizations as a possible arrhythmia mechanism (Vaidyanathan et al 2018). Intriguingly, the two Cav3 mutations investigated can have distinct effects on the sensitive ionic currents, with Cav3-F97C causing a reduction in I Kv4.3 , whereas Cav3-S141R had no effect on I Kv4.3 .…”

Section: Lqts9 Cav3 Mutations Apd Prolongation and Arrhythmiasmentioning

confidence: 99%

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Long QT syndrome caveolin‐3 mutations differentially modulate K_v4 and Ca_v1.2 channels to contribute to action potential prolongation

Tyan

Foell

Vincent

et al. 2019

The Journal of Physiology

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Key points Mutations in the caveolae scaffolding protein, caveolin‐3 (Cav3), have been linked to the long QT type 9 inherited arrhythmia syndrome (LQT9) and the cause of underlying action potential duration prolongation is incompletely understood. In the present study, we show that LQT9 Cav3 mutations, F97C and S141R, cause mutation‐specific gain of function effects on Cav1.2‐encoded L‐type Ca2+ channels responsible for ICa,L and also cause loss of function effects on heterologously expressed Kv4.2 and Kv4.3 channels responsible for Ito. A computational model of the human ventricular myocyte action potential suggests that the major ionic current change causing action potential duration prolongation in the presence of Cav3‐F97C is the slowly inactivating ICa,L but, for Cav3‐S141R, both increased ICa,L and increased late Na+ current contribute equally to action potential duration prolongation. Overall, the LQT9 Cav3‐F97C and Cav3‐S141R mutations differentially impact multiple ionic currents, highlighting the complexity of Cav3 regulation of cardiac excitability and suggesting mutation‐specific therapeutic approaches. Abstract Mutations in the CAV3 gene encoding caveolin‐3 (Cav3), a scaffolding protein integral to caveolae in cardiomyocytes, have been associated with the congenital long‐QT syndrome (LQT9). Initial studies demonstrated that LQT9‐associated Cav3 mutations, F97C and S141R, increase late sodium current as a potential mechanism to prolong action potential duration (APD) and cause LQT9. Whether these Cav3 LQT9 mutations impact other caveolae related ion channels remains unknown. We used the whole‐cell, patch clamp technique to characterize the effect of Cav3‐F97C and Cav3‐S141R mutations on heterologously expressed Cav1.2+Cavβ2cN4 channels, as well as Kv4.2 and Kv4.3 channels, in HEK 293 cells. Expression of Cav3‐S141R increased ICa,L density without changes in gating properties, whereas expression of Cav3‐F97C reduced Ca2+‐dependent inactivation of ICa,L without changing current density. The Cav3‐F97C mutation reduced current density and altered the kinetics of IKv4.2 and IKv4.3 and also slowed recovery from inactivation. Cav3‐S141R decreased current density and also slowed activation kinetics and recovery from inactivation of IKv4.2 but had no effect on IKv4.3. Using the O'Hara–Rudy computational model of the human ventricular myocyte action potential, the Cav3 mutation‐induced changes in Ito are predicted to have negligible effect on APD, whereas blunted Ca2+‐dependent inactivation of ICa,L by Cav3‐F97C is predicted to be primarily responsible for APD prolongation, although increased ICa,L and late INa by Cav3‐S141R contribute equally to APD prolongation. Thus, LQT9 Cav3‐associated mutations, F97C and S141R, produce mutation‐specific changes in multiple ionic currents leading to different primary causes of APD prolongation, which suggests the use of mutation‐specific therapeutic approaches in the future.

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“…Highly orchestrated trafficking processes ensure that cardiac ion channels are expressed on appropriate membrane domains at suitable densities to maintain the electrical rhythm of the heart. Targeting of the inward rectifying potassium channel, Kir2.1, to the t-tubule and sarcolemma in ventricular myocytes ( Ma et al, 2011 ), for example, is made possible by a series of sequential processes that deliver newly synthesized channels from the endoplasmic reticulum to the Golgi ( Ma et al, 2001 ), control trans -Golgi network (TGN) to the cell surface ( Ma et al, 2011 ), and drive association with appropriate lipid domains ( Vaidyanathan et al, 2013 , 2018 ; Han et al, 2014 ) and scaffolding complexes ( Leonoudakis et al, 2004a , b ; Rubi et al, 2017 ). The importance of membrane trafficking is underscored by human disease; mutations in Kir2.1 that disrupt proper trafficking ( Bendahhou et al, 2003 ; Ballester et al, 2006 ; Ma et al, 2011 ) cause Andersen–Tawil syndrome ( Plaster et al, 2001 ), which predisposes affected patients to cardiac arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

Golgin-97 Targets Ectopically Expressed Inward Rectifying Potassium Channel, Kir2.1, to the trans-Golgi Network in COS-7 Cells

Taneja

Kim

et al. 2018

Front. Physiol.

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The inward rectifying potassium channel, Kir2.1, is selected as cargo at the trans-Golgi network (TGN) for export to the cell surface through a unique signal-dependent interaction with the AP1 clathrin-adaptor, but it is unknown how the channel is targeted at earlier stages in the secretory pathway for traffic to the TGN. Here we explore a mechanism. A systematic screen of Golgi tethers identified Golgin-97 as a Kir2.1 binding partner. In vitro protein-interaction studies revealed the interaction is direct, occurring between the GRIP domain of Golgin-97 and the cytoplasmic domain of Kir2.1. Imaging and interaction studies in COS-7 cells suggest that Golgi-97 binds to the channel en route through the Golgi. RNA interference-mediated knockdown of Golgin-97 prevented exit of Kir2.1 from the Golgi. These observations identify Golgin-97 as a Kir2.1 binding partner that is required for targeting the channel to the TGN. Based on our studies in COS-7 cells, we propose Golgi-97 facilitates formation of AP1-dependent export carriers for Kir2.1 by coupling anterograde delivery of Kir2.1 with retrograde recycling of AP-1 containing endosomes to the TGN.

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Inward Rectifier Potassium Channels (Kir2.x) and Caveolin-3 Domain–Specific Interaction

Cited by 29 publications

References 60 publications

Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel

Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel

Long QT syndrome caveolin‐3 mutations differentially modulate K_v4 and Ca_v1.2 channels to contribute to action potential prolongation

Golgin-97 Targets Ectopically Expressed Inward Rectifying Potassium Channel, Kir2.1, to the trans-Golgi Network in COS-7 Cells

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Inward Rectifier Potassium Channels (Kir2.x) and Caveolin-3 Domain–Specific Interaction

Cited by 29 publications

References 60 publications

Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel

Caveolin-3 Microdomain: Arrhythmia Implications for Potassium Inward Rectifier and Cardiac Sodium Channel

Long QT syndrome caveolin‐3 mutations differentially modulate Kv4 and Cav1.2 channels to contribute to action potential prolongation

Golgin-97 Targets Ectopically Expressed Inward Rectifying Potassium Channel, Kir2.1, to the trans-Golgi Network in COS-7 Cells

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Long QT syndrome caveolin‐3 mutations differentially modulate K_v4 and Ca_v1.2 channels to contribute to action potential prolongation