EHD3-Dependent Endosome Pathway Regulates Cardiac Membrane Excitability and Physiology

Curran, James F.; Makara, Michael; Little, Sean C.; Musa, Hassan; Liu, Bin; Wu, Xuan; Polina, Iuliia; Alecusan, Joseph S.; Wright, Patrick; Li, Jingdong; Boyden, Penelope A.; Györke, Sándor; Band, Hamid; Hund, Thomas J.; Mohler, Peter J.

doi:10.1161/circresaha.115.304149

Cited by 33 publications

(36 citation statements)

References 40 publications

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“…Moreover, the differing molecular composition of cavin complexes across cell types [e.g., cardiomyocytes express all cavin isoforms except for cavin 3 (22,48)] suggests that additional proteins contribute to caveolae formation and confer tissue-specific functions (49). For instance, EHD2, a member of the EHD family of endosomal recycling proteins (50) recently reported to regulate cardiac membrane protein targeting (51,52), has been shown to interact with cavin 1 and control the stability and turnover of caveolae (53). Our data contribute to the expanding list of caveolae regulators and establish FGF13 as a noncavin protein in heart that regulates caveolae density by tuning the balance of cavin 1 between membrane and cytosol.…”

Section: Discussionmentioning

confidence: 99%

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na + channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found-even in the context of the expected reduction in Na + channel current-an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling. (1), share a core domain with homology to canonical FGFs, but FHFs are not secreted, do not bind or activate FGF receptors, and do not function as growth factors (2). Instead, FHFs bind directly to voltage-gated Na + channels, modulating channel gating and trafficking (3, 4). Widely expressed in the brain (1), FHFs have been implicated in neurologic diseases such as spinocerebellar ataxia 27, caused by missense mutations in FGF14 that diminish Na + channel current, disrupt channel localization, and impair neuronal excitability (5-7).In addition to their broad distribution in the central nervous system, FHFs are expressed in the mammalian heart (1). Their roles in regulating cardiac function, however, have only been recently investigated. We showed that FGF13, the predominant FHF in rodent heart and a common transcript in human heart (8), directly binds to the C terminus of cardiac Na V 1.5 Na + channels, and thereby regulates current density and conduction velocity by affecting channel gating and surface expression (9). Similarly, mutations that disrupt interaction between Na V 1.5 and FGF12, the major human cardiac FHF, have been linked to lifethreatening arrhythmia syndromes (8, 10). In addition to regulating Na + channels, FHFs can modulate voltage-gated Ca 2+ channels (11, 12). Fgf13 knockdown in adult rodent ventricular cardiomyocytes decreased Ca V 1.2 current density, perturbed Ca V 1.2 localization at the dyad, and thereby affected Ca 2+ -induced Ca 2+ release (11). Because previous studies were conducted in cultured cardiomyocytes, however, the in vivo roles for FHFs in ...

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Section: Discussionmentioning

confidence: 99%

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Wei

Sinden

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Immunoblots of whole-ventricle tissue lysates were analyzed on Mini-PROTEAN Tetra Cell (Bio-Rad) on a 4 to 15% TGX precast gel (Bio-Rad) in tris/glycine/SDS buffer (Bio-Rad) as described (30). Antibodies included the following: PP2A/A (Calbiochem 539509), PP2A–C subunit (1:500, Millipore 05-421), PPP2R5A (1:500, Abcam ab72028), PPP2R5C (1:500, Abcam ab94633), PME-1 (1–500, Abcam ab154569), LCMT-1 (1:500, OriGene clone 209), CaMKIId (1:1000, Santa Cruz Biotechnology SC-13082), PKA catalytic (1:2500, R&D Systems MAB5908), SERCA2 (1:2000, Pierce Antibodies IID8), PLB (1:10,000, Abcam ab2865), PLB Ser 16 (1:20,000, Badrilla A010-12), PLB Ser 17 (1:20,000, Badrilla A010-13) (31), RyR 2 (1:1000, Millipore), and GAPDH (1:5000, Fitzgerald).…”

Section: Methodsmentioning

confidence: 99%

Protein phosphatase 2A regulatory subunit B56α limits phosphatase activity in the heart

et al. 2015

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Protein phosphatase 2A (PP2A) is a serine/threonine-selective holoenzyme composed of a catalytic, scaffolding, and regulatory subunit. In the heart, PP2A activity is requisite for cardiac excitation-contraction coupling and central in adrenergic signaling. We found that mice deficient in the PP2A regulatory subunit B56α (1 of 13 regulatory subunits) had altered PP2A signaling in the heart that was associated with changes in cardiac physiology, suggesting that the B56α regulatory subunit had an autoinhibitory role that suppressed excess PP2A activity. The increase in PP2A activity in the mice with reduced B56α expression resulted in slower heart rates and increased heart rate variability, conduction defects, and increased sensitivity of heart rate to parasympathetic agonists. Increased PP2A activity in B56α+/− myocytes resulted in reduced Ca2+ waves and sparks, which was associated with decreased phosphorylation (and thus decreased activation) of the ryanodine receptor RyR2, an ion channel on intracellular membranes that is involved in Ca2+ regulation in cardiomyocytes. In line with an autoinhibitory role for B56α, in vivo expression of B56α in the absence of altered abundance of other PP2A subunits decreased basal phosphatase activity. Consequently, in vivo expression of B56α suppressed parasympathetic regulation of heart rate and increased RyR2 phosphorylation in cardiomyocytes. These data show that an integral component of the PP2A holoenzyme has an important inhibitory role in controlling PP2A enzyme activity in the heart.

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“…Furthermore, Ca v 1.2 expression and function is reduced in a mouse model of cardiac-specific deficiency of EHD3, an endosomal protein that binds and traffics AnkB. 24, 25 Alterations in calcium signaling due to dysregulation of the RyR2 are attributed to enhanced coupling of RyR2 openings in AnkB +/− cardiomyocytes. 26 RyR2 pS1814 phosphorylation by calcium/calmodulin-dependent kinase (CaMKII) may also be amplified in AnkB +/− mice, potentially via disruption of the AnkB-dependent B56α targeting mechanism.…”

Section: Role Of Ankyrin-b In Cardiac Excitabilitymentioning

confidence: 99%

The evolving role of ankyrin-B in cardiovascular disease

Koenig

Mohler

2017

Heart Rhythm

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Over the last decade, ankyrin-B has been identified as a prominent player in cardiac physiology. Ankyrin-B has a multitude of functions, with roles in expression, localization, and regulation of proteins critical for cardiac excitability, cytoskeletal integrity, and signaling. Further, human ANK2 variants that result in ankyrin-B loss-of-function are associated with ‘Ankyrin-B syndrome’, a complex cardiac phenotype that may include bradycardia and heart rate variability, conduction block, atrial fibrillation, QT interval prolongation, and potentially fatal catecholaminergic polymorphic ventricular tachycardia. However, our understanding of the molecular mechanisms underlying ankyrin-B function at baseline and in disease is still not fully resolved due to the complexity of ankyrin-B gene regulation, number of ankyrin-B-associated molecules, multiple roles of ankyrin-B in the heart and other organs that modulate cardiac function, and a host of unexpected clinical phenotypes. Here, we summarize known roles of ankyrin-B in the heart and the impact of ankyrin-B dysfunction in animal models and in human disease, as well as highlight important new findings illustrating the complexity of ankyrin-B signaling.

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EHD3-Dependent Endosome Pathway Regulates Cardiac Membrane Excitability and Physiology

Cited by 33 publications

References 40 publications

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload

Protein phosphatase 2A regulatory subunit B56α limits phosphatase activity in the heart

The evolving role of ankyrin-B in cardiovascular disease

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