Fig. 8: Neuronal Ca²⁺ signaling in heart failure.

Increased catecholamine levels during HF activate PKA, which phosphorylates RyR2 on Ser2808 (Fig. 3). Increased inflammation in HF includes activation of the TGF-β pathway resulting in SMAD3 phosphorylation and upregulation of NOX2 and binding to RyR2 (Extended Data Fig. 4). NOX2 promotes oxidation of RyR2 channels^58,59,60. The combination of oxidation and phosphorylation of RyR2 results in ER Ca²⁺ leak (Fig. 3). Ca²⁺ leak through RyR2 leads to increased mitochondrial Ca²⁺ accumulation, which enhances mitochondrial ROS production (Extended Data Fig. 10). Therefore, a vicious cycle is created between the mitochondria and RyR2, where increased ER Ca²⁺ leak causes mitochondrial ROS production and increased mitochondrial ROS production further oxidizes RyR2 and renders it leakier. Chronic RyR2 Ca²⁺ leak depletes ER Ca²⁺ content and reduces the Ca²⁺ transient (Fig. 5) required for synaptic vesicle release during synaptic transmission (Figs. 4 and 7). Furthermore, oxidative stress and Ca²⁺ dyshomeostasis alter gene transcription (Extended Data Fig. 7), with a particular effect on proteins that are regulated by Ca²⁺ and involved in neurotransmission. Dysregulation of key proteins involved in synaptic transmission is reflected in the impaired LTP observed in the MI mice (Fig. 4b,c). Accumulation of Ca²⁺ in the cytosol activates Ca²⁺-dependent enzymes including CAMKII, GSK-β, CDK5 and p25, which subsequently leads to Tau phosphorylation, a hallmark of neurodegenerative disease (Supplementary Figs. 9 and 10). All these activated signaling cascades can be prevented, at least in part, by S107, a Rycal drug that reduces the ER Ca²⁺ leak. Gs, G protein; AC, adenylyl cyclase; cAMP, cyclic AMP; GSK-β, glycogen synthase kinase 3 beta. Created with BioRender.com.