BIN1 Localizes the L-Type Calcium Channel to Cardiac T-Tubules

Hong, Ting Ting; Smyth, J. D.; Gao, Danchen; Chu, Kevin Y.; Vogan, Jacob M.; Fong, Tina S.; Jensen, Brian C.; Colecraft, Henry M.; Shaw, Robin M.

doi:10.1371/journal.pbio.1000312

Cited by 207 publications

(288 citation statements)

References 54 publications

(76 reference statements)

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“…7 and 8). Similar images were published in murine and human ventricular cardiomyocytes with Ca v 1.2 expression in the ttubules [69]. The accidental co-localization of the channel proteins due to technical factors of imaging is unlikely since the co-localization of TMEM16A with cytochrome c was weak (Supplementary Fig.…”

Section: Ca 2+ -Entry Via I Cal Is Essential For the Activation Of Isupporting

confidence: 69%

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

Horváth

Váczi

Hegyi

et al. 2016

Journal of Molecular and Cellular Cardiology

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Highlights• Ca 2+ -entry via I Ca,L is essential for the activation of I Cl(Ca) • I Cl(Ca) can be activated even in the absence of CICR• TMEM16A and Bestrophin-3 are expressed on human left ventricular muscle• TMEM16A and Bestrophin-3 co-localize with each other and with Ca v 1.2 channels (I Cl(Ca) ) mediated by TMEM16A and/or Bestrophin-3 may contribute to cardiac arrhythmias. The true profile of I Cl(Ca) during an actual ventricular action potential (AP), however, is poorly understood. We aimed to study the profile of I Cl(Ca) systematically under physiological conditions (normal Ca 2+ cycling and AP voltage-clamp) as well as in conditions designed to change [Ca 2+ ] i . The expression of TMEM16A and/or Bestrophin-3 in canine and human left ventricular myocytes was examined. The possible spatial distribution of these proteins and their co-localization with Ca v 1.2 was also studied. The profile of I Cl(Ca), identified as a 9-anthracene carboxylic acid-sensitive current under AP voltageclamp conditions, contained an early fast outward and a late inward component, overlapping early and terminal repolarizations, respectively. Both components were moderately reduced by ryanodine, while fully abolished by BAPTA, but not EGTA. [Ca 2+ ] i was monitored using Fura-2-AM. Setting [Ca 2+ ] i to the systolic level measured in the bulk cytoplasm (1.1 µM) decreased I Cl(Ca), while application of Bay K8644, isoproterenol, and faster stimulation rates increased the amplitude of I Cl(Ca) . Ca 2+ -entry through L-type Ca 2+ channels was essential for activation of I Cl(Ca) . TMEM16A and Bestrophin-3 showed strong co-localization with one another and also with Ca v 1.2 channels, when assessed using immunolabeling and confocal microscopy in both canine myocytes and human ventricular myocardium. Activation of I Cl(Ca) in canine ventricular cells requires Ca 2+ -entry through neighboring L-type Ca 2+ channels and is only augmented by SR Ca 2+ -release. Substantial activation of I Cl(Ca) requires high Ca 2+ in the dyadic clefts which can be effectively buffered by BAPTA, but not EGTA.

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Section: Ca 2+ -Entry Via I Cal Is Essential For the Activation Of Isupporting

confidence: 69%

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

Horváth

Váczi

Hegyi

et al. 2016

Journal of Molecular and Cellular Cardiology

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“…BIN1 has been implicated in many cellular processes, such as inducing membrane invagination (Frost et al, 2009) and initiating tubulogenesis in skeletal muscle cells (Lee et al, 2002). In human and mouse heart cells, BIN1 localizes to cardiac t-tubules (Hong et al, 2010), forms t-tubule membrane microdomains (Hong et al, 2014;Fu et al, 2016), facilitates cytoskeleton-based calcium channel trafficking to t-tubule membrane (Hong et al, 2010), and causes RyR movement along the SR membrane (Fu et al, 2016).…”

Section: Bin1 and Its Different Isoformsmentioning

confidence: 99%

“…In "Targeted Delivery", channel delivery to a specific membrane subdomain requires the dynamic microtubule highway and its coordination with channel itself and a particular membrane anchor protein. In the case of LTCC trafficking, LTCC-carrying microtubules are attracted to BIN1 at t-tubule membrane (Hong et al, 2010). Once tethered to BIN1, microtubules unload their cargo calcium channels to BIN1 protein at the membrane.…”

Section: The Role Of Bin1 In T-tubule Microdomain Organization and Fumentioning

confidence: 99%

Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health

Zhou

Hong

2016

Sci. China Life Sci.

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In recent decades, a cardiomyocyte membrane scaffolding protein bridging integrator 1 (BIN1) has emerged as a critical multifunctional regulator of transverse-tubule (t-tubule) function and calcium signaling in cardiomyocytes. Encoded by a single gene with 20 exons that are alternatively spliced, more than ten BIN1 protein isoforms are expressed with tissue and disease specificity. The recently discovered cardiac alternatively spliced isoform BIN1 (cBIN1 or BIN1+13+17)plays a crucial role in organizing membrane microfolds within cardiac t-tubules. These cBIN1-induced microfolds form functional dyad microdomains by trafficking L-type calcium channels (LTCC) to t-tubule membrane and recruiting ryanodine receptors (RyR) to junctional sarcoplasmic reticulum membrane. When cBIN1 is transcriptionally reduced as occurs in heart failure, cBIN1-microfolds are disrupted and fail to form LTCC and RyR couplons. As a result, impaired dyad formation limits excitation-contraction coupling thus cardiac contractility, and accumulation of orphaned leaky RyRs outside of dyads increases ventricular arrhythmias. Reduced myocardial BIN1 in heart failure is also detectable at the blood level, and plasma BIN1 level predicts heart failure progression and future arrhythmias in cardiomyopathy patients. Here we will review the recent progress in BIN1-related cardiomyocyte biology studies and discuss the diagnostic and predictive values of cBIN1 in future clinical use. heart failure, cBIN1, t-tubules, calcium transient, arrhythmias Citation:Zhou, K., and Hong, T. (2017). Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health.

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“…There is currently no invasive or noninvasive tool that measures intrinsic cardiomyocyte health. cBIN1 is an integral protein in cardiomyocyte t-tubule biology [20,21] and beat-to-beat calcium transients [29][30][31]. Previously, our group found that BIN1 is transcriptionally decreased in HF and is also detectable in blood [22,23].…”

Section: Discussionmentioning

confidence: 98%

“…The cardiac isoform of bridging integrator 1 (cBIN1) is a t-tubule membrane sculpting protein, which organizes microdomains and proteins responsible for calcium release and excitationcontraction coupling [20,21]. cBIN1 is transcriptionally decreased in failing hearts [22] and is also detectable in blood [23,24].…”

Section: Introductionmentioning

confidence: 99%

Plasma cBIN1 Score (CS) Identifies HFrEF and Can Predict Cardiac Hospitalization in Stable Ambulatory Patients

Xie¹,

Hitzeman²,

Zadikany³

et al. 2018

Preprint

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Objective: We determined, in stable ambulatory heart failure with reduced ejection fraction (HFrEF) subjects and matched controls, the capability of a novel blood based cardiac-specific cBIN1 Score (CS), which assesses the health of cardiac muscle, to identify patients with known heart failure (HF) and to prognosticate future hospitalization.Background: Limited clinical tools are available in assessing cardiac muscle health in stable

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BIN1 Localizes the L-Type Calcium Channel to Cardiac T-Tubules

Abstract: Cardiac tubular-like membrane invaginations contain the membrane scaffolding protein BIN1, which tethers dynamic microtubules that deliver calcium channels directly to T-tubule membrane.

Cited by 207 publications

References 54 publications

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

Cardiac BIN1 (cBIN1) is a regulator of cardiac contractile function and an emerging biomarker of heart muscle health

Plasma cBIN1 Score (CS) Identifies HFrEF and Can Predict Cardiac Hospitalization in Stable Ambulatory Patients

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