T-tubules and ryanodine receptor microdomains: on the road to translation.

The concept of localized signalling in the coupling between L-type Ca2+ channels, LTCC, in the sarcolemma and ryanodine receptors, RyR, in the sarcoplasmic reticulum was introduced in the late 1980s to address one of the conundrums of excitation–contraction coupling. The tightly regulated Ca2+ signals observed in isolated cardiac myocytes under voltage clamp conditions, or in skinned myocytes, were hard to explain in a global control cell model in which intracellular calcium is uniform everywhere at all time. However, they could be understood in a concept of local control within a microdomain as proposed in the theoretical studies by Stern and others. Concomitant insight into the ultrastructure of the dyadic cleft and gating properties of single LTCC and RyR channels provided the critical elements to develop the microdomain concept where clusters of RyR interact with clusters of LTCC in the dyad. Such a functional unit was termed a couplon, consisting of clusters of RyR and LTCC in close juxtaposition ( 12 nm) of the two membranes. Sparks, spontaneous Ca2+ release events from RyR, were the first visualization of the local events and were typically associated with the dyad near T-tubules (TTs). Spurred by improved imaging of Ca2+ signals and of myocyte ultrastructure, and by computational modelling and genetic manipulations, our knowledge on the characteristics and functional impact of microdomain signalling near TTs has grown tremendously. The evidence that modulation and remodelling of these microdomains is involved in global cardiac dysfunction in hypertrophy and failure has further fuelled research. This spotlight issue gives an update of current knowledge emphasizing the outlook for signalling and cardiac remodelling, and highlighting the novel and emerging research directions.