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Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.

Hong T, Yang H, Zhang SS, Cho HC, Kalashnikova M, Sun B, Zhang H, Bhargava A, Grabe M, Olgin J, Gorelik J, Marbán E, Jan LY, Shaw RM - Nat. Med. (2014)

Bottom Line: Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts.We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs.When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.

View Article: PubMed Central - PubMed

Affiliation: 1] Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. [2].

ABSTRACT
Cardiomyocyte T tubules are important for regulating ion flux. Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts. Here we find that cardiac T tubules normally contain dense protective inner membrane folds that are formed by a cardiac isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased, which does not change overall cardiomyocyte morphology but leads to free diffusion of local extracellular calcium and potassium ions, prolonging action-potential duration and increasing susceptibility to ventricular arrhythmias. We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs. BIN1+13+17 recruits actin to fold the T-tubule membrane, creating a 'fuzzy space' that protectively restricts ion flux. When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.

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Ventricular arrhythmias induced by pacing and beta adrenergic activation with isoproterenol. (a) Representative recordings of EKG following a S1–S4 stimulation protocol. Normal sinus node beats resume immediately following pacing in WT mice (top panel), sustained monomorphic ventricular tachycardia (4.5 s) was induced in Bin1 HT mice (middle panel), sustained polymorphic ventricular tachycardia (VT) alternating with ventricular fibrillation (VF) (>20s) was induced in Bin1 HO mice (bottom panel). (b) Heart rate increase (∆HR) in response to isoproterenol was analyzed and compared among the three groups (mean ± SEM, n = 3–4, P = 0.04 by one-way ANOVA). (c) Incidence of sustained VT (>9 QRS) or VF in each group (n = 3–4, P = 0.03 by chi-square). (d) The frequency of ventricular arrhythmias before and after isoproterenol treatment was quantified in each group (n = 3–4, P < 0.01 by two-way ANOVA).
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Figure 4: Ventricular arrhythmias induced by pacing and beta adrenergic activation with isoproterenol. (a) Representative recordings of EKG following a S1–S4 stimulation protocol. Normal sinus node beats resume immediately following pacing in WT mice (top panel), sustained monomorphic ventricular tachycardia (4.5 s) was induced in Bin1 HT mice (middle panel), sustained polymorphic ventricular tachycardia (VT) alternating with ventricular fibrillation (VF) (>20s) was induced in Bin1 HO mice (bottom panel). (b) Heart rate increase (∆HR) in response to isoproterenol was analyzed and compared among the three groups (mean ± SEM, n = 3–4, P = 0.04 by one-way ANOVA). (c) Incidence of sustained VT (>9 QRS) or VF in each group (n = 3–4, P = 0.03 by chi-square). (d) The frequency of ventricular arrhythmias before and after isoproterenol treatment was quantified in each group (n = 3–4, P < 0.01 by two-way ANOVA).

Mentions: Given the effects of BIN1 reduction on ion homeostasis and membrane potential prolongation, we next studied in vivo arrhythmogenesis in WT, Bin1 HT and Bin1 HO mice subjected to ventricular pacing before and after intra-myocardial injection of isoproterenol. As is evident from the representative EKG recordings (Fig. 4a), sinus rhythm resumes immediately after ectopic pacing in WT mice (top panel). However, sustained monomorphic ventricular tachycardia (VT) ensues after pacing in Bin1 HT mice (middle panel), and more severe sustained polymorphic VT alternating with ventricular fibrillation (VF) occurs in Bin1 HO mice (bottom panel). The overall incidence of sustained VT (>9 consecutive wide-complex beats)31,32 or VF (Fig. 4c), as well as the frequency of pacing-induced arrhythmias (Fig. 4d), were significantly increased in Bin1 HT and HO mice. Bin1 deletion also dramatically increased isoproterenol-induced arrhythmias (Fig. 4d), which have been linked to LTCC-mediated afterdepolarizations33.


Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia.

Hong T, Yang H, Zhang SS, Cho HC, Kalashnikova M, Sun B, Zhang H, Bhargava A, Grabe M, Olgin J, Gorelik J, Marbán E, Jan LY, Shaw RM - Nat. Med. (2014)

Ventricular arrhythmias induced by pacing and beta adrenergic activation with isoproterenol. (a) Representative recordings of EKG following a S1–S4 stimulation protocol. Normal sinus node beats resume immediately following pacing in WT mice (top panel), sustained monomorphic ventricular tachycardia (4.5 s) was induced in Bin1 HT mice (middle panel), sustained polymorphic ventricular tachycardia (VT) alternating with ventricular fibrillation (VF) (>20s) was induced in Bin1 HO mice (bottom panel). (b) Heart rate increase (∆HR) in response to isoproterenol was analyzed and compared among the three groups (mean ± SEM, n = 3–4, P = 0.04 by one-way ANOVA). (c) Incidence of sustained VT (>9 QRS) or VF in each group (n = 3–4, P = 0.03 by chi-square). (d) The frequency of ventricular arrhythmias before and after isoproterenol treatment was quantified in each group (n = 3–4, P < 0.01 by two-way ANOVA).
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Related In: Results  -  Collection

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Show All Figures
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Figure 4: Ventricular arrhythmias induced by pacing and beta adrenergic activation with isoproterenol. (a) Representative recordings of EKG following a S1–S4 stimulation protocol. Normal sinus node beats resume immediately following pacing in WT mice (top panel), sustained monomorphic ventricular tachycardia (4.5 s) was induced in Bin1 HT mice (middle panel), sustained polymorphic ventricular tachycardia (VT) alternating with ventricular fibrillation (VF) (>20s) was induced in Bin1 HO mice (bottom panel). (b) Heart rate increase (∆HR) in response to isoproterenol was analyzed and compared among the three groups (mean ± SEM, n = 3–4, P = 0.04 by one-way ANOVA). (c) Incidence of sustained VT (>9 QRS) or VF in each group (n = 3–4, P = 0.03 by chi-square). (d) The frequency of ventricular arrhythmias before and after isoproterenol treatment was quantified in each group (n = 3–4, P < 0.01 by two-way ANOVA).
Mentions: Given the effects of BIN1 reduction on ion homeostasis and membrane potential prolongation, we next studied in vivo arrhythmogenesis in WT, Bin1 HT and Bin1 HO mice subjected to ventricular pacing before and after intra-myocardial injection of isoproterenol. As is evident from the representative EKG recordings (Fig. 4a), sinus rhythm resumes immediately after ectopic pacing in WT mice (top panel). However, sustained monomorphic ventricular tachycardia (VT) ensues after pacing in Bin1 HT mice (middle panel), and more severe sustained polymorphic VT alternating with ventricular fibrillation (VF) occurs in Bin1 HO mice (bottom panel). The overall incidence of sustained VT (>9 consecutive wide-complex beats)31,32 or VF (Fig. 4c), as well as the frequency of pacing-induced arrhythmias (Fig. 4d), were significantly increased in Bin1 HT and HO mice. Bin1 deletion also dramatically increased isoproterenol-induced arrhythmias (Fig. 4d), which have been linked to LTCC-mediated afterdepolarizations33.

Bottom Line: Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts.We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs.When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.

View Article: PubMed Central - PubMed

Affiliation: 1] Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. [2].

ABSTRACT
Cardiomyocyte T tubules are important for regulating ion flux. Bridging integrator 1 (BIN1) is a T-tubule protein associated with calcium channel trafficking that is downregulated in failing hearts. Here we find that cardiac T tubules normally contain dense protective inner membrane folds that are formed by a cardiac isoform of BIN1. In mice with cardiac Bin1 deletion, T-tubule folding is decreased, which does not change overall cardiomyocyte morphology but leads to free diffusion of local extracellular calcium and potassium ions, prolonging action-potential duration and increasing susceptibility to ventricular arrhythmias. We also found that T-tubule inner folds are rescued by expression of the BIN1 isoform BIN1+13+17, which promotes N-WASP-dependent actin polymerization to stabilize the T-tubule membrane at cardiac Z discs. BIN1+13+17 recruits actin to fold the T-tubule membrane, creating a 'fuzzy space' that protectively restricts ion flux. When the amount of the BIN1+13+17 isoform is decreased, as occurs in acquired cardiomyopathy, T-tubule morphology is altered, and arrhythmia can result.

Show MeSH
Related in: MedlinePlus