Eps15 Homology Domain-containing Protein 3 Regulates Cardiac T-type Ca2+ Channel Targeting and Function in the Atria

Curran, James F.; Musa, Hassan; Kline, Crystal F.; Makara, Michael; Little, Sean C.; Higgins, John D.; Hund, Thomas J.; Band, Hamid; Mohler, Peter J.

doi:10.1074/jbc.m115.646893

Cited by 14 publications

(16 citation statements)

References 69 publications

(38 reference statements)

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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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“…To date, only EHD3 has been described to have a functional role in this tissue. EHD3 binds to ankyrins, which, in turn, stabilizes the Na + /Ca 2+ exchanger (NCX1) and Ca 2+ channels at the sarcolemma (14,15). Expression of EHD2 has previously been noted in isolated adult cardiac myocytes, including human, with subcellular localization to perinuclear regions and z lines (14).…”

Section: Ehd2 Regulates Endogenous Cardiomyocyte K Atp Channels and Pmentioning

confidence: 99%

“…EHD2 has also been described to regulate the exit of cargo from the ERC en route to the cell surface (10). Each of the 4 EHD proteins are expressed in the heart (14); however, to date, only EHD3 has been characterized and demonstrated to regulate the surface density of the Na + /Ca 2+ exchanger and the T-type Ca 2+ channel (14,15). Given that EHD proteins are components of the K ATP channel macromolecular complex (5,6), we examined the possibility that they regulate K ATP channel trafficking and surface density.…”

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confidence: 99%

The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K _ATP channel surface expression: role in cardioprotection

et al. 2018

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ATP-sensitive K (K) channels uniquely link cellular energy metabolism to membrane excitability and are expressed in diverse cell types that range from the endocrine pancreas to neurons and smooth, skeletal, and cardiac muscle. A decrease in the surface expression of K channels has been linked to various disorders, including dysregulated insulin secretion, abnormal blood pressure, and impaired resistance to cardiac injury. In contrast, up-regulation of K channel surface expression may be protective, for example, by mediating the beneficial effect of ischemic preconditioning. Molecular mechanisms that regulate K channel trafficking are poorly understood. Here, we used cellular assays with immunofluorescence, surface biotinylation, and patch clamping to demonstrate that Eps15 homology domain-containing protein 2 (EHD2) is a novel positive regulator of K channel trafficking to increase surface K channel density. EHD2 had no effect on cardiac Na channels (Nav1.5). The effect is specific to EHD2 as other members of the EHD family-EHD1, EHD3, and EHD4-had no effect on K channel surface expression. EHD2 did not directly affect K channel properties as unitary conductance and ATP sensitivity were unchanged. Instead, we observed that the mechanism by which EHD2 increases surface expression is by stabilizing K channel-containing caveolar structures, which results in a reduced rate of endocytosis. EHD2 also regulated K channel trafficking in isolated cardiomyocytes, which validated the physiologic relevance of these observations. Pathophysiologically, EHD2 may be cardioprotective as a dominant-negative EHD2 mutant sensitized cardiomyocytes to ischemic damage. Our findings highlight EHD2 as a potential pharmacologic target in the treatment of diseases with K channel trafficking defects.-Yang, H. Q., Jana, K., Rindler, M. J., Coetzee, W. A. The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K channel surface expression: role in cardioprotection.

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“…Heterozygosity of AnkB in mouse sinoatrial node and atrial myocytes is associated with reduced expression of 12, 32 Additionally, Ca v 1.3.cardiac-specific deletion of EHD3 results in dysregulated expression and localization of Ca v 3.1 and Ca v 3.2 and reduced T-type mediated Ca 2+ current. 33 AnkB +/− mice display sinus node and atrial electrophysiological dysfunction, abnormal SAN electrical activity (including altered diastolic depolarization), shortened atrial action potentials, atrial fibrosis, and increased susceptibility to atrial fibrillation. 12, 32, 34 Additionally, Glukhov et al found that isoproterenol-treated AnkB +/− mice exhibited competing multiple pacemakers and beat-to-beat variability within the leading pacemaker.…”

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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Eps15 Homology Domain-containing Protein 3 Regulates Cardiac T-type Ca2+ Channel Targeting and Function in the Atria

Cited by 14 publications

References 69 publications

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

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

The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K _ATP channel surface expression: role in cardioprotection

The evolving role of ankyrin-B in cardiovascular disease

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Eps15 Homology Domain-containing Protein 3 Regulates Cardiac T-type Ca2+ Channel Targeting and Function in the Atria

Cited by 14 publications

References 69 publications

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

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

The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K ATP channel surface expression: role in cardioprotection

The evolving role of ankyrin-B in cardiovascular disease

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The trafficking protein, EHD2, positively regulates cardiac sarcolemmal K _ATP channel surface expression: role in cardioprotection