Connexin 43 and CaV1.2 Ion Channel Trafficking in Healthy and Diseased Myocardium

Basheer, Wassim A.; Shaw, Robin M.

doi:10.1161/circep.115.001357

Cited by 27 publications

(28 citation statements)

References 127 publications

(161 reference statements)

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“…Targeted delivery of ion channels to the appropriate subdomain requires three components: a cytoskeleton delivery apparatus, a membrane anchor, and the channel itself 11, 38 . Previously, we identified that key components of targeted delivery of Cx43 hemichannels to the ventricular intercalated disc include microtubules which are captured by the membrane anchor adherens junctions complex including N-Cadherin, β-catenin and p150 (Glued) 17, 18 .…”

Section: Discussionmentioning

confidence: 99%

GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs

Basheer

Xiao

Epifantseva

et al. 2017

Circulation Research

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108

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Rationale Delivery of connexin 43 (Cx43) to the intercalated disc is a continuous and rapid process critical for intercellular coupling. By a pathway of targeted delivery involving microtubule highways, vesicles of Cx43 hemichannels are efficiently trafficked to adherens junctions at intercalated discs. It has also been identified that actin provides rest stops for Cx43 forward trafficking, and that Cx43 has a 20kDa internally translated small C-terminus isoform (GJA1-20k) which is required for full-length Cx43 trafficking, but by an unknown mechanism. Objective We explored the mechanism by which the GJA1-20k isoform is required for full-length Cx43 forward trafficking to intercalated discs. Methods and Results Using an in-vivo AAV9-mediated gene transfer system, we confirmed in whole animal that GJA1-20k markedly increases endogenous myocardial Cx43 gap junction plaque size at the intercalated discs. In micropatterned cell pairing systems, we found that exogenous GJA1-20k expression stabilizes filamentous actin (F-actin) without affecting actin protein expression, and that GJA1-20k complexes with both actin and tubulin. We also found that F-actin regulates microtubule organization as inhibition of actin polymerization with a low dose of latrunculin A (LatA) disrupts the targeting of microtubules to cell-cell junctions. GJA1-20k protects actin filament from LatA disruption, preserving microtubule trajectory to the cell-cell border. For therapeutic implications, we found that prior in vivo AAV9-mediated gene delivery of GJA1-20k to the heart protects Cx43 localization to the intercalated discs against acute ischemic injury. Conclusions The internally translated GJA1-20k isoform stabilizes actin filaments which guides growth trajectories of the Cx43 microtubule trafficking machinery, increasing delivery of Cx43 hemichannels to cardiac intercalated discs. Exogenous GJA1-20k helps to maintain cell-cell coupling in instances of anticipated myocardial ischemia.

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Section: Discussionmentioning

confidence: 99%

GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs

Basheer

Xiao

Epifantseva

et al. 2017

Circulation Research

Self Cite

108

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“…Mice bearing homozygous deletions of either gene die at embryonic stages ( Larsen et al., 2002 , Link et al., 2009 , Rusconi et al., 2016 , Seisenberger et al., 2000 , Weissgerber et al., 2006 ). In humans, aberrant calcium permeation through Ca V 1.2 channels is associated with several pathological cardiac conditions ( Basheer and Shaw, 2016 , Dick et al., 2016 , Hofmann et al., 2014 , Hong et al., 2012 , Shaw and Colecraft, 2013 , Splawski et al., 2004 , Splawski et al., 2005 ). The function and number of channels at the plasma membrane regulates the amount of calcium entering into the cardiomyocytes.…”

Section: Introductionmentioning

confidence: 99%

“…Defective trafficking of the cardiac Ca V 1.2 channel protein has been linked to disorders including atrial fibrillation, heart failure, and Brugada syndrome ( Antzelevitch et al., 2007 , Basheer and Shaw, 2016 , Schotten et al., 2003 , Simms and Zamponi, 2012 , Xiao and Shaw, 2015 ). Thus, elucidation of the pathway by which Ca V 1.2 traffics to and from the plasma membrane is very relevant to understanding heart function and dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Rapid Turnover of the Cardiac L-Type CaV1.2 Channel by Endocytic Recycling Regulates Its Cell Surface Availability

et al. 2018

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SummaryCalcium entry through CaV1.2 L-type calcium channels regulates cardiac contractility. Here, we study the impact of exocytic and post-endocytic trafficking on cell surface channel abundance in cardiomyocytes. Single-molecule localization and confocal microscopy reveal an intracellular CaV1.2 pool tightly associated with microtubules from the perinuclear region to the cell periphery, and with actin filaments at the cell cortex. Channels newly inserted into the plasma membrane become internalized with an average time constant of 7.5 min and are sorted out to the Rab11a-recycling compartment. CaV1.2 recycling suffices for maintaining stable L-type current amplitudes over 20 hr independent of de novo channel transport along microtubules. Disruption of the actin cytoskeleton re-routes CaV1.2 from recycling toward lysosomal degradation. We identify endocytic recycling as essential for the homeostatic regulation of voltage-dependent calcium influx into cardiomyocytes. This mechanism provides the basis for a dynamic adjustment of the channel's surface availability and thus, of heart's contraction.

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“…The number of ion channels on the membrane of a cardiomyocyte that determine the cardiac AP is dynamically regulated via trafficking, degradation, and recycling pathways [ 11 , 12 ]. For several ion channels it has been established that the composition of the macromolecular complex plays a major role in their trafficking.…”

Section: Common Components Of Macromolecular Complexesmentioning

confidence: 99%

Ion channels as part of macromolecular multiprotein complexes

Heijman

Dobrev

2017

Herzschr Elektrophys

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Ion channels and Ca2+-handling proteins involved in the regulation of cardiac electrophysiology and contractility are organized in macromolecular multiprotein complexes. Recent molecular and cellular studies have significantly enhanced our understanding of the composition of these macromolecular complexes and have helped to elucidate their role in the dynamic regulation of ion channel function. Moreover, it has become clear that alterations in the composition of ion channel macromolecular complexes, for example, due to genetic mutations or acquired alterations in the expression of individual components, may lead to ion channel dysfunction and arrhythmogenesis. Here, we review novel insights into the composition of the major ion channel macromolecular complexes and discuss the potential clinical significance of alterations in these dynamic multiprotein structures.

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Connexin 43 and CaV1.2 Ion Channel Trafficking in Healthy and Diseased Myocardium

Cited by 27 publications

References 127 publications

GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs

GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs

Rapid Turnover of the Cardiac L-Type CaV1.2 Channel by Endocytic Recycling Regulates Its Cell Surface Availability

Ion channels as part of macromolecular multiprotein complexes

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