Abstract
Remodelling of the membranes and protein clustering patterns during the pathogenesis of cardiomyopathies has renewed the interest in spatial visualisation of these structures in cardiomyocytes. Coincidental emergence of single molecule (super-resolution) imaging and tomographic electron microscopy tools in the last decade have led to a number of new observations on the structural features of the couplons, the primary sites of excitation-contraction coupling in the heart. In particular, super-resolution and tomographic electron micrographs have revised and refined the classical views of the nanoscale geometries of couplons, t-tubules and the organisation of the principal calcium handling proteins in both healthy and failing hearts. These methods have also allowed the visualisation of some features which were too small to be detected with conventional microscopy tools. With new analytical capabilities such as single-protein mapping, in situ protein quantification, correlative and live cell imaging we are now observing an unprecedented interest in adapting these research tools across the cardiac biophysical research discipline. In this article, we review the depth of the new insights that have been enabled by these tools toward understanding the structure and function of the cardiac couplon. We outline the major challenges that remain in these experiments and emerging avenues of research which will be enabled by these technologies.
Highlights
Coined as a name for the focal contacts between the sarcolemma and the sarcoplasmic reticulum (SR) of skeletal muscle (Stern et al, 1997), the term ‘couplon’ in the present day relates more broadly to the nanodomains which encompass the fast calcium (Ca2+) signalling mechanisms in striated muscle cells
There was, a striking change in the co-localisation between L-type Ca2+ channels (LCC) and RyR as well as structural proteins of the couplon in the cells exhibiting t-tubule remodelling, examined with confocal microscopy (Song et al, 2006; van Oort et al, 2011; Crossman et al, 2015b)
We demonstrated that differences in the diameters and the degree of tubule branching was clearly observable between the species
Summary
Coined as a name for the focal contacts between the sarcolemma and the sarcoplasmic reticulum (SR) of skeletal muscle (Stern et al, 1997), the term ‘couplon’ in the present day relates more broadly to the nanodomains which encompass the fast calcium (Ca2+) signalling mechanisms in striated muscle cells. An optimised approach to confocal imaging (Chen-Izu et al, 2006), had further revealed couplons, reported by clustered RyR were organised throughout the entire transverse aspect of the Z-discs, much closer to each other (∼600–700 nm) than the previously assumed sarcomeric spacings (∼1.8 μm; Chen-Izu et al, 2006; Soeller et al, 2007; Figures 1B,C) These observations, together with the demonstration of nonplanar arrangement of the z-lines at the transverse plane of cardiomyocytes (Soeller et al, 2009; Jayasinghe et al, 2010) led to a series of geometrically realistic simulations of spontaneous propagating Ca2+ release (Ca2+ waves) throughout the volumes of myocytes (Izu et al, 2006; Soeller et al, 2009; Li et al, 2010). There was, a striking change in the co-localisation between LCCs and RyR as well as structural proteins of the couplon (e.g., junctophilin-2; JPH2) in the cells exhibiting t-tubule remodelling, examined with confocal microscopy (Song et al, 2006; van Oort et al, 2011; Crossman et al, 2015b)
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