Dependence of Cardiac Transverse Tubules on the BAR Domain Protein Amphiphysin II (BIN-1)

Abstract

T he synchronous rise of the systolic Ca 2+ transient in mammalian ventricular myocytes requires the presence of an extensive and regular transverse (t)-tubular system.1 These t-tubules ensure close apposition of L-type Ca 2+ channels (LTCCs) and sarcoplasmic reticulum (SR) Ca 2+ release channels (ryanodine receptors [RyRs]) forming dyads or couplons where excitation-contraction coupling commences.2,3 The t-tubules are also surrounded by a continuous network of SR, which is thought to assist with amplification of the initial Ca 2+ entry during the action potential and contribute to the synchronous rise of systolic Ca 2+ . 4,5The t-tubule and SR networks are, however, labile with disorganization and loss commonly observed in heart failure (HF). [5][6][7][8][9] In such circumstances the loss of t-tubules leads to dyssynchronous Ca 2+ release patterns, a smaller systolic Ca 2+ transient, and altered β-adrenergic (β-adrenergic receptor) signaling. 6-10 Conversely, recovery from HF is associated with restoration of the t-tubule network along with normalization of β-adrenergic receptor signaling and resynchronization of the systolic Ca 2+ transient. 9,11In This Issue, see p 961More extensive differences in t-tubule organization and density than those occurring in the ventricle during HF are known to exist between the atrium and the ventricle. For example, small mammals (mouse, rat, rabbit, etc) completely lack or possess only a rudimentary, predominantly axially arranged, t-tubule network.2-14 Conversely, some studies have suggested that limited numbers of atrial cells from smaller laboratory species such as the rat have a more ventricular-like t-tubule pattern, 15 although these particular cells may be of different lineage and a feature of the pulmonary vein sleeve region. 16The poorly developed t-tubule network in these atrial myocytes leads to the characteristic early peripheral and delayed central Rationale: Transverse tubules (t-tubules) regulate cardiac excitation-contraction coupling and exhibit interchamber and interspecies differences in expression. In cardiac disease, t-tubule loss occurs and affects the systolic calcium transient. However, the mechanisms controlling t-tubule maintenance and whether these factors differ between species, cardiac chambers, and in a disease setting remain unclear.Objective: To determine the role of the Bin/Amphiphysin/Rvs domain protein amphiphysin II (AmpII) in regulating t-tubule maintenance and the systolic calcium transient. Methods and Results:T-tubule density was assessed by di-4-ANEPPS, FM4-64 or WGA staining using confocal microscopy. In rat, ferret, and sheep hearts t-tubule density and AmpII protein levels were lower in the atrium than in the ventricle. Heart failure (HF) was induced in sheep using right ventricular tachypacing and ferrets by ascending aortic coarctation. In both HF models, AmpII protein and t-tubule density were decreased in the ventricles. In the sheep, atrial t-tubules were also lost in HF and AmpII levels decreased. Conversely, junctophilin 2 leve...

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

“…We propose that increases in JPH2 and improvements in t‐tubule morphology mediate the augmented RV function, which is further supported by the significant relationships between JPH2 and RV function (Figure 5). These results agree with several studies showing that reduced levels of JPH2 are associated with left ventricular dysfunction in animal models36, 37, 38, 39, 40 and human disease states15, 41 and that increased expression of JPH2, achieved via transgenic overexpression,19 antagonism of miR‐24,42 viral‐mediated overexpression,20 or inhibition of calpain proteases,43 improves cardiac function in animal models of LV dysfunction. Thus, increased JPH2 likely mediates the improved RV‐PA coupling in MCT‐colchicine rats.…”

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

“…Some studies indicate that JPH2 is down-regulated in animal models of hypertrophic and dilated cardiomyopathy , and conditional knockdown of JPH2 in the heart causes systolic heart failure in murine models . Other studies report no significant changes of JPH2 expression in failing hearts (Caldwell et al, 2014), or Zhou, K., et al Sci China Life Sci March (2017) Vol. 60 No.…”

“…This protective ionic diffusion barrier becomes even more significant during fast pacing states where restricted diffusion can effectively limit a quick depletion of extracellular calcium ions, preventing loss of transmembrane ionic flux. When cBIN1 is reduced as occurs in HF Lyon et al, 2012;Caldwell et al, 2014), not only channel localization to dyads is impaired, but also removal of the diffusion barrier can deplete extracellular ions, further diminishing LTCC current and impairing CICR (Figure 2, bottom panel).…”

“…Later, a decrease in BIN1 transcription was identified in acquired human HF and multiple animal models of HF (Lyon et al, 2012;Caldwell et al, 2014), which recovers during functional recovery (Lyon et al, 2012). In failing cardiomyocytes, decreased BIN1 level impairs LTCC trafficking Lyon et al, 2012;Caldwell et al, 2014), diminishing calcium transients. In zebrafish, knockdown of Bin1 induces significant contractile dysfunction and cardiomyopathy .…”

Transverse tubule remodelling: a cellular pathology driven by both sides of the plasmalemma?

“…At the molecular scale, several candidate proteins have been identified that are required for normal junctional structure and appear to be involved in t-tubule remodelling in heart failure (van Oort et al 2011;Zhang et al 2014;Hong et al 2014;Wu et al 2014;Guo et al 2014;Caldwell et al 2014). The first of these proteins identified was junctophilin-2 (JPH2), a protein that forms a connection between the plasma and SR membranes.…”