FIGURE 6.

Schematic demonstrating the speculated state of a t-tubular microdomain in loaded or unloaded scenarios with or without isoprenaline stimulation. (1) Loaded cell. LTCC are generally active within the tubule owning to some constitutive cAMP production and consequent PKA activity, scaffolded by Cav-3 and JPH-2. Calcium spark activity at the sarcoplasmic reticulum is nominal. (2) Unloaded cell. LTCC are generally inactive as there is a loss of coherent confinement of cAMP and PKA activity to the t-tubular microdomain. This is due to the mechanosensitivity of the association between Cav1.2, Cav-3, and JPH-2 and the loss of t-tubules. Even though there is a smaller amount of LTCC activity spark activity increases as orphaned RyR no longer receive effective control and thus experience a gain of function. (3) Loaded cell stimulated with ISO. After stimulation β2AR increase cAMP levels in the cytoplasm of the sarcomeric dyad and this activates a sub-population of PKA which activates almost all LTCC. Spark activity remains nominal as effective measures to control LTCC and RYR phosphorylation and the degradation of cAMP remain effective due to scaffolding by the cellular microdomain. (4) Unloaded cell stimulated with ISO. Despite a reduction in the amount of cAMP response initiated by β₂AR in the cytosol, signals still reach RII_PKA domains, due to the loss of efficient cAMP compartmentation. This stimulates further aberrant spark activity due to the relatively uncontrolled calcium influx in the cell and EC mediator hyperphosphorylation following the loss of normal structure within the sarcomeric dyad following unloading.