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. 2019 Jan 3;115(12):1778–1790. doi: 10.1093/cvr/cvy306

Figure 7.

Figure 7

Schematic showing proposed changes of cAMP/PKA signalling in 2- and 12-month-old NTG or AC8TG animals. (A) In healthy cardiomyocytes major cAMP/PKA events are confined in the interspace T-tubule/junctional reticulum controlling inotropic response via LTCC and RyR phosphorylation. (B) In AC8TG, cAMP produced by AC8 is confined at the level of LR, having access to the SERCA2a/PLN compartment, but not to LTCC compartment. SERCA2A/PLN compartment is delimited by PDE1A&C, PDE3B and PDE4D. The benefit effect of PLN phosphorylation in AC8TG is hampered by phosphorylation GSK3α&β, apparently located in the same compartment. (C) In early compensated age-related dysfunction, the effective junctional reticulum/T-tubule microdomain confining is lost, leading to channelling of cAMP towards LR and increased PLN phosphorylation in order to compensate for the loss of contractile function and degradation of tissue condition. However, GSK3 phosphorylation hampers this compensating adaptation via induction of hypertrophy-, fibrosis-, and ageing-related pathways.