There Goes the Neighborhood: Pathological Alterations in T-Tubule Morphology and Consequences for Cardiomyocyte Ca^𝟐+ Handling

Figure 1

Schematic representation of the dyadic neighborhood in normal and failing cells. (a) Excitation-contraction coupling occurs at functional junctions between Ca²⁺ channels in the T-tubules and ryanodine receptors in the SR. Depending on their localization, other proteins in the dyadic neighborhood such as SR Ca²⁺ ATPase (SERCA), NCX, NKA, and Na⁺ channels can also regulate Ca²⁺ homeostasis. Question mark: The positioning of the Na⁺ channel at the dyad is still controversial. (b) During heart failure, T-tubule loss and/or disorganization occurs leading to the formation of orphaned ryanodine receptors, which do not have apposing Ca²⁺ channels. Ca²⁺ release in these regions is delayed leading to slower and weaker contractions. Other putative alterations in the dyadic neighborhood are indicated by the question marks: (1) it is unclear whether the Na⁺ channel is present in the dyad of failing cardiomyocytes. Some experimental evidence suggests that the distance between the SR and T-tubule is increased in heart failure (2), while T-tubule disorganization may lead to dyadic clefts with variable width (3).