Trafficking Highways to the Intercalated Disc: New Insights Unlocking the Specificity of Connexin 43 Localization

Zhang, Shanshan; Shaw, Robin M.

doi:10.3109/15419061.2013.876014

Cited by 23 publications

(18 citation statements)

References 150 publications

(210 reference statements)

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“…As shown in Fig. 7, immunoreactive signals for SAP97 were concentrated at the cell surface in control myocytes, similar to the previously reported localization of this protein to intercalated discs in adult rat ventricular myocardium (22). However, there was a marked decrease in the amount of SAP97 signal at the cell surface in myocytes expressing 2057del2 plakoglobin, which was fully reversed by exposing myocytes to SB216763 for 24 hours (Fig.…”

Section: Resultssupporting

confidence: 90%

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Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy

et al. 2014

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Arrhythmogenic cardiomyopathy (ACM) is characterized by frequent cardiac arrhythmias. To elucidate the underlying mechanisms and discover potential chemical modifiers, we created a zebrafish model of ACM with cardiac myocyte–specific expression of the human 2057del2 mutation in the gene encoding plakoglobin. A high-throughput screen identified SB216763 as a suppressor of the disease phenotype. Early SB216763 therapy prevented heart failure and reduced mortality in the fish model. Zebrafish ventricular myocytes that expressed 2057del2 plakoglobin exhibited 70 to 80% reductions in INa and IK1 current densities, which were normalized by SB216763. Neonatal rat ventricular myocytes that expressed 2057del2 plakoglobin recapitulated pathobiological features seen in patients with ACM, all of which were reversed or prevented by SB216763. The reverse remodeling observed with SB216763 involved marked subcellular redistribution of plakoglobin, connexin 43, and Nav1.5, but without changes in their total cellular content, implicating a defect in protein trafficking to intercalated discs. In further support of this mechanism, we observed SB216763-reversible, abnormal subcellular distribution of SAP97 (a protein known to mediate forward trafficking of Nav1.5 and Kir2.1) in rat cardiac myocytes expressing 2057del2 plakoglobin and in cardiac myocytes derived from induced pluripotent stem cells from two ACM probands with plakophilin-2 mutations. These observations pinpoint aberrant trafficking of intercalated disc proteins as a central mechanism in ACM myocyte injury and electrical abnormalities.

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Section: Resultssupporting

confidence: 90%

“…This suggests a unique relationship between plakoglobin and SAP97 not shared by other desmosomal linker proteins. Finally, knockdown of SAP97 expression had no effect on the distribution of Cx43, whose trafficking is known to involve a different transport mechanism (22). …”

Section: Resultsmentioning

confidence: 99%

Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy

et al. 2014

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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%

“…Growing evidence supports a cytoskeletal-based trafficking mechanism for Cx43 delivery directly to the intercalated disc 10, 11 . It is understood that Cx43 hemichannels oligomerize in the trans-Golgi network 12 , and are subsequently packaged into vesicles transported by motor proteins along microtubules 13–15 .…”

Section: Introductionmentioning

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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“…We cannot rule out that other pathways of Cx43 trafficking and GJ life cycle, besides phosphorylation, are affected, including microtubule-dependent forward trafficking to the junctional plaques. 36…”

Section: Potential Molecular Mechanismmentioning

confidence: 99%

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

Crassous

Shu

Huang

et al. 2017

JAHA

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BackgroundGuanylyl cyclase, a heme‐containing α1β1 heterodimer (GC1), produces cGMP in response to Nitric oxide (NO) stimulation. The NO‐GC1‐cGMP pathway negatively regulates cardiomyocyte contractility and protects against cardiac hypertrophy–related remodeling. We recently reported that the β1 subunit of GC1 is detected at the intercalated disc with connexin 43 (Cx43). Cx43 forms gap junctions (GJs) at the intercalated disc that are responsible for electrical propagation. We sought to determine whether there is a functional association between GC1 and Cx43 and its role in cardiac homeostasis.Methods and Results GC1 and Cx43 immunostaining at the intercalated disc and coimmunoprecipitation from membrane fraction indicate that GC1 and Cx43 are associated. Mice lacking the α subunit of GC1 (GCα1 knockout mice) displayed a significant decrease in GJ function (dye‐spread assay) and Cx43 membrane lateralization. In a cardiac‐hypertrophic model, angiotensin II treatment disrupted the GC1‐Cx43 association and induced significant Cx43 membrane lateralization, which was exacerbated in GCα1 knockout mice. Cx43 lateralization correlated with decreased Cx43‐containing GJs at the intercalated disc, predictors of electrical dysfunction. Accordingly, an ECG revealed that angiotensin II–treated GCα1 knockout mice had impaired ventricular electrical propagation. The phosphorylation level of Cx43 at serine 365, a protein‐kinase A upregulated site involved in trafficking/assembly of GJs, was decreased in these models.Conclusions GC1 modulates ventricular Cx43 location, hence GJ function, and partially protects from electrical dysfunction in an angiotensin II hypertrophy model. Disruption of the NO‐cGMP pathway is associated with cardiac electrical disturbance and abnormal Cx43 phosphorylation. This previously unknown NO/Cx43 signaling could be a protective mechanism against stress‐induced arrhythmia.

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Trafficking Highways to the Intercalated Disc: New Insights Unlocking the Specificity of Connexin 43 Localization

Cited by 23 publications

References 150 publications

Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy

Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy

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

Newly Identified NO‐Sensor Guanylyl Cyclase/Connexin 43 Association Is Involved in Cardiac Electrical Function

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