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Chemotherapy-induced cognitive dysfunction (chemobrain) is an important adverse sequela of chemotherapy. Chemobrain has been identified by the National Cancer Institute as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Here, we show that chemotherapy treatment with doxorubicin (DOX) in a breast cancer mouse model induced protein kinase A (PKA) phosphorylation of the neuronal ryanodine receptor/calcium (Ca2+) channel type 2 (RyR2), RyR2 oxidation, RyR2 nitrosylation, RyR2 calstabin2 depletion, and subsequent RyR2 Ca2+ leakiness. Chemotherapy was furthermore associated with abnormalities in brain glucose metabolism and neurocognitive dysfunction in breast cancer mice. RyR2 leakiness and cognitive dysfunction could be ameliorated by treatment with a small molecule Rycal drug (S107). Chemobrain was also found in noncancer mice treated with DOX or methotrexate and 5-fluorouracil and could be prevented by treatment with S107. Genetic ablation of the RyR2 PKA phosphorylation site (RyR2-S2808A) also prevented the development of chemobrain. Chemotherapy increased brain concentrations of the tumor necrosis factor–α and transforming growth factor–β signaling, suggesting that increased inflammatory signaling might contribute to oxidation-driven biochemical remodeling of RyR2. Proteomics and Gene Ontology analysis indicated that the signaling downstream of chemotherapy-induced leaky RyR2 was linked to the dysregulation of synaptic structure–associated proteins that are involved in neurotransmission. Together, our study points to neuronal Ca2+ dyshomeostasis via leaky RyR2 channels as a potential mechanism contributing to chemobrain, warranting further translational studies. Editor's summary: Cancer survivors often experience cognitive impairments after chemotherapy, and these side effects are commonly known as chemobrain. Here, Liu and colleagues treated breast cancer mice and wild-type mice with two chemotherapeutic regimens (doxorubicin or methotrexate and 5-fluorouricil) to investigate the role of ryanodine receptor type 2 (RyR2) in chemobrain. The authors identified chemotherapy-induced posttranslational modifications and increased calcium leakiness of RyR2. Treatment with a ryanodine receptor calcium release channel stabilizer (S107) prevented chemotherapy-induced RyR2 leakiness and ameliorated cognitive deficits in these breast cancer mice. The authors found similar chemotherapy-induced RyR2 modifications and cognitive deficits in cancer free mice, indicating that chemotherapy without cancer is sufficient to induce chemobrain in mice. These preclinical results suggest that targeting RyR2 might be a promising target to prevent chemobrain. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

The article presents a study on the structural analyses of human ryanodine receptor type 2 channels and their correlation with sudden cardiac death. It describes the mechanism for catecholaminergic polymorphic ventricular tachycardia (CPVT) and the therapeutic actions of ARM210. Mechanism of action of drug-induced stabilization of RyR2 receptor channels and a role for xanthine in this.