Localization of telokin at the intercalated discs of cardiac myocytes

Kargacin, Gary J.; Hunt, Donald J.; Emmett, Teresa; Rokolya, Anikó; McMartin, Gail A.; Wirch, Erwin; Walsh, Michael P.; Ikebe, Mitsuo; Kargacin, Margaret E.

doi:10.1016/j.abb.2006.06.018

Cited by 5 publications

(5 citation statements)

References 45 publications

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“…(B) Percentage of N-cadherin and mXinβ distributed in each peak at different developmental stages. A developmental increase of N-cadherin in the peak I indicates that peak I contains the mature ICDs, consistent with the previous identification of this peak fraction by electron microscopy (Kargacin et al, 2006). After P18.5, a larger proportion of mXinβ than N-cadherin is associated with peak I.…”

Section: Figsupporting

confidence: 91%

The Xin repeat-containing protein, mXinβ, initiates the maturation of the intercalated discs during postnatal heart development

Wang

Lin

Chan

et al. 2013

Developmental Biology

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The intercalated disc (ICD) is a unique structure to the heart and plays vital roles in communication and signaling among cardiomyocytes. ICDs are formed and matured during postnatal development through a profound redistribution of the intercellular junctions, as well as recruitment and assembly of more than 200 proteins at the termini of cardiomyocytes. The molecular mechanism underlying this process is not completely understood. The mouse orthologs (mXinα and mXinβ) of human cardiomyopathy-associated (CMYA)/Xin actin-binding repeat-containing protein (XIRP) genes (CMYA1/XIRP1 and CMYA3/XIRP2, respectively) encode proteins localized to ICDs. Ablation of mXinα results in adult late-onset cardiomyopathy with conduction defects and up-regulation of mXinβ. ICD structural defects are found in adult but not juvenile mXinα-null hearts. On the other hand, loss of mXinβ leads to ICD defects at postnatal day 16.5, a developmental stage when the heart is forming ICDs, suggesting mXinβ is required for ICD formation. Using quantitative Western blot, we showed in this study that mXinβ but not mXinα was uniquely up-regulated during the redistribution of intercellular junction from the lateral membrane of cardiomyocytes to their termini. In the absence of mXinβ, the intercellular junctions failed to be restricted to the termini of the cells, and the onset of such defect correlated with the peak expression of mXinβ. Immunofluorescence staining and subcellular fractionation showed that mXinβ preferentially associated with the forming ICDs, further suggesting that mXinβ functioned locally to promote ICD maturation. In contrast, the spatiotemporal expression profile of mXinα and the lack of more severe ICD defects in mXinα−/−;mXinβ−/− double knockout hearts than in mXinβ−/− hearts suggested that mXinα was not essential for the postnatal formation of ICDs. A two-step model for the development of ICD is proposed where mXinβ is essential for the redistribution of intercellular junction components from the lateral puncta to the cell termini.

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Section: Figsupporting

confidence: 91%

The Xin repeat-containing protein, mXinβ, initiates the maturation of the intercalated discs during postnatal heart development

Wang

Lin

Chan

et al. 2013

Developmental Biology

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“…Total protein and ID enriched fractions were isolated using previous methods [24,25]. Immunodetection of the indicated proteins was performed as described [24].…”

Section: Methodsmentioning

confidence: 99%

Novel obscurins mediate cardiomyocyte adhesion and size via the PI3K/AKT/mTOR signaling pathway

Ackermann

King

Lieberman

et al. 2017

Journal of Molecular and Cellular Cardiology

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The intercalated disc of cardiac muscle embodies a highly-ordered, multifunctional network, essential for the synchronous contraction of the heart. Over 200 known proteins localize to the intercalated disc. The challenge now lies in their characterization as it relates to the coupling of neighboring cells and whole heart function. Using molecular, biochemical and imaging techniques, we characterized for the first time two small obscurin isoforms, obscurin-40 and obscurin-80, which are enriched at distinct locations of the intercalated disc. Both proteins bind specifically and directly to select phospholipids via their pleckstrin homology (PH) domain. Overexpression of either isoform or the PH-domain in cardiomyocytes results in decreased cell adhesion and size via reduced activation of the PI3K/AKT/mTOR pathway that is intimately linked to cardiac hypertrophy. In addition, obscurin-80 and obscurin-40 are significantly reduced in acute (myocardial infarction) and chronic (pressure overload) murine cardiac-stress models underscoring their key role in maintaining cardiac homeostasis. Our novel findings implicate small obscurins in the maintenance of cardiomyocyte size and coupling, and the development of heart failure by antagonizing the PI3K/AKT/mTOR pathway.

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“…To facilitate this integrated model, over 200 additional proteins reside at the ID, including but not limited to ion channels, i.e., Na v 1.5, scaffolding proteins, i.e., vinculin, spectrins, ankyrins, zona occludens (ZO)-1, and obscurins, and signaling molecules, i.e., CaMKII, PKCα, and TGFβ (Ackermann et al 2017a, b;Bennett et al 2006;Dowling et al 2008;Estigoy et al 2009;Geisler et al 2007;Jung-Ching Lin et al 2005;Kargacin et al 2006;Lange et al 2016;Satomi-Kobayashi et al 2009;Schroen et al 2007;Seeger et al 2010;Vermij et al 2017). Together, these highly organized proteins along with the convoluted nature of the ID membrane allow for the formation of a single functional unit facilitating complex inter-and intracellular signals.…”

Section: Introductionmentioning

confidence: 99%

At the heart of inter- and intracellular signaling: the intercalated disc

et al. 2018

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Proper cardiac function requires the synchronous mechanical and electrical coupling of individual cardiomyocytes. The intercalated disc (ID) mediates coupling of neighboring myocytes through intercellular signaling. Intercellular communication is highly regulated via intracellular signaling, and signaling pathways originating from the ID control cardiomyocyte remodeling and function. Herein, we present an overview of the inter- and intracellular signaling that occurs at and originates from the intercalated disc in normal physiology and pathophysiology. This review highlights the importance of the intercalated disc as an integrator of signaling events regulating homeostasis and stress responses in the heart and the center of several pathophysiological processes mediating the development of cardiomyopathies.

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Localization of telokin at the intercalated discs of cardiac myocytes

Cited by 5 publications

References 45 publications

The Xin repeat-containing protein, mXinβ, initiates the maturation of the intercalated discs during postnatal heart development

The Xin repeat-containing protein, mXinβ, initiates the maturation of the intercalated discs during postnatal heart development

Novel obscurins mediate cardiomyocyte adhesion and size via the PI3K/AKT/mTOR signaling pathway

At the heart of inter- and intracellular signaling: the intercalated disc

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