EH Domain Proteins Regulate Cardiac Membrane Protein Targeting

Gudmundsson, Hjalti; Hund, Thomas J.; Wright, Patrick; Kline, Crystal F.; Snyder, John P.; Lei, Qian; Koval, Olha M.; Cunha, Shane R.; George, Manju; Rainey, Mark A.; Kashef, Farshid; Dun, Wen; Boyden, Penelope A.; Anderson, Mark E.; Band, Hamid; Mohler, Peter J.

doi:10.1161/circresaha.110.216713

Cited by 63 publications

(74 citation statements)

References 36 publications

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“…siRNA-siRNA recognizing PP2A/A, PP2A/C, PPP2R3A, PPP2R4, PPP2R5C, and PPP2R5E (siGENOME, Dharmacon) were individually transfected into neonatal cardiomyocytes using Effectene (39).…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

DeGrande

Little

Nixon

et al. 2013

Journal of Biological Chemistry

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Background: PP2A regulates cardiac excitability and physiology. Results: PP2A regulation in heart occurs through integrative transcriptional, translational, and post-translational control of three classes of subunits (17 genes) to control holoenzyme synthesis, localization, and maintenance; pathways are mechanistically altered in heart disease. Conclusion:Multiple mechanisms are present for acute and chronic regulation of specific PP2A populations. Significance: Results provide molecular insight into cardiac PP2A regulation.

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“…siRNA-siRNA recognizing PP2A/A, PP2A/C, PPP2R3A, PPP2R4, PPP2R5C, and PPP2R5E (siGENOME, Dharmacon) were individually transfected into neonatal cardiomyocytes using Effectene (39).…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

DeGrande

Little

Nixon

et al. 2013

Journal of Biological Chemistry

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“…Vectors were completely sequenced. RNA was isolated and processed for RT-PCR as described previously, using oligo-dT to prime for cDNA production (71). Primers to identify βIV-spectrin transcripts in heart and brain include primers directed against the N terminus to recognize full-length βIVΣ1-spectrin in rat (forward, 5′-GGGATGGCTTT-GTCCTCACCC-3′; reverse, 5′-GCCAAGAGTTCCAACTTCTCC-3′; nucleotides 271-1,226 in rat [βIV-spectrin-Spnb4; XM_218364], product shown in Figure 2) as well as C-terminal primers that recognize βIVΣ1-spectrin and βIVΣ6-spectrin in mouse (βIV-spectrin-Spnb4; NM_032610) and rat (forward, 5′-CCACGATCGAGAAACTCAAGG-3′; reverse, 5′-GGTGTCCGTC-GTGTCCAACG-3′; not shown).…”

Section: Computational Analysis Of Putativementioning

confidence: 99%

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

Hund¹,

Koval²,

Li³

et al. 2010

J. Clin. Invest.

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229

289

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Ion channel function is fundamental to the existence of life. In metazoans, the coordinate activities of voltagegated Na + channels underlie cellular excitability and control neuronal communication, cardiac excitationcontraction coupling, and skeletal muscle function. However, despite decades of research and linkage of Na + channel dysfunction with arrhythmia, epilepsy, and myotonia, little progress has been made toward understanding the fundamental processes that regulate this family of proteins. Here, we have identified β IV -spectrin as a multifunctional regulatory platform for Na + channels in mice. We found that β IV -spectrin targeted critical structural and regulatory proteins to excitable membranes in the heart and brain. Animal models harboring mutant β IV -spectrin alleles displayed aberrant cellular excitability and whole animal physiology. Moreover, we identified a regulatory mechanism for Na + channels, via direct phosphorylation by β IV -spectrin-targeted calcium/calmodulin-dependent kinase II (CaMKII). Collectively, our data define an unexpected but indispensable molecular platform that determines membrane excitability in the mouse heart and brain.

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“…EHD1 and EHD4 null mice both exhibit defects in spermatogenesis and decreased male fertility (George et al , 2010; Rainey et al , 2010). siRNA reduction of EHD3 in cardiomyocytes indicated that EHD3 has a role in the trafficking of the cardiac ankyrin-B membrane protein (Gudmundsson et al , 2010). In addition, EHD3 and EHD4 were sufficiently elevated following myocardial infarction, suggesting that these molecules may have a role in cardiomyocyte damage response.…”

Section: Ferlin Proteins In Cytoskeletal Rearrangements During Myomentioning

confidence: 99%

Ferlin Proteins in Myoblast Fusion and Muscle Growth

Posey¹,

Demonbreun²,

McNally³

2011

Current Topics in Developmental Biology

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Myoblast fusion contributes to muscle growth in development and during regeneration of mature muscle. Myoblasts fuse to each other as well as to multinucleate myotubes to enlarge the myofiber. The molecular mechanisms of myoblast fusion are incompletely understood. Adhesion, apposition, and membrane fusion are accompanied by cytoskeletal rearrangements. The ferlin family of proteins is implicated in human muscle disease and has been implicated in fusion events in muscle, including myoblast fusion, vesicle trafficking and membrane repair. Dysferlin was the first mammalian ferlin identified and it is now know that there are six different ferlins. Loss of function mutations in the dysferlin gene lead to limb girdle muscular dystrophy and the milder disorder Miyoshi myopathy. Dysferlin is a membrane-associated protein that has been implicated in resealing disruptions in the muscle plasma membrane. Newer data supports a broader role for dysferlin in intracellular vesicular movement, a process also important for resealing. Myoferlin is highly expressed in myoblasts that undergoing fusion, and the absence of myoferlin leads to impaired myoblast fusion. Myoferlin also regulates intracellular trafficking events, including endocytic recycling, a process where internalized vesicles are returned to the plasma membrane. The trafficking role of ferlin proteins is reviewed herein with a specific focus as to how this machinery alters myogenesis and muscle growth.

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EH Domain Proteins Regulate Cardiac Membrane Protein Targeting

Abstract: Rationale: Cardiac membrane excitability is tightly regulated by an integrated network of membrane-associated ion channels, transporters, receptors, and signaling molecules.

Cited by 63 publications

References 36 publications

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

Molecular Mechanisms Underlying Cardiac Protein Phosphatase 2A Regulation in Heart

A βIV-spectrin/CaMKII signaling complex is essential for membrane excitability in mice

Ferlin Proteins in Myoblast Fusion and Muscle Growth

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