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Liu, Xiaoping; Betzenhauser, Matthew J.; Reiken, Steve; Meli, Albano C.; Xie, Wenjun; Chen, Bi-Xing; Arancio, Ottavio; Marks, Andrew R.
Cell, 08/2012, Letnik: 150, Številka: 5Journal Article
The type 2 ryanodine receptor/calcium release channel (RyR2), required for excitation-contraction coupling in the heart, is abundant in the brain. Chronic stress induces catecholamine biosynthesis and release, stimulating β-adrenergic receptors and activating cAMP signaling pathways in neurons. In a murine chronic restraint stress model, neuronal RyR2 were phosphorylated by protein kinase A (PKA), oxidized, and nitrosylated, resulting in depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the channel complex and intracellular calcium leak. Stress-induced cognitive dysfunction, including deficits in learning and memory, and reduced long-term potentiation (LTP) at the hippocampal CA3-CA1 connection were rescued by oral administration of S107, a compound developed in our laboratory that stabilizes RyR2-calstabin2 interaction, or by genetic ablation of the RyR2 PKA phosphorylation site at serine 2808. Thus, neuronal RyR2 remodeling contributes to stress-induced cognitive dysfunction. Leaky RyR2 could be a therapeutic target for treatment of stress-induced cognitive dysfunction. Display omitted ► Leaky hippocampal RyR2 channels contribute to stress-induced cognitive dysfunction ► RyR2 PKA hyperphosphorylation and calstabin2 depletion cause intracellular Ca2+ leak ► Pharmacologic or genetic inhibition of Ca2+ leak prevent the cognitive dysfunction Stabilizing a leaky calcium release channel with a small molecule alleviates the detrimental effects of long-term stress on learning and memory.
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in: SICRIS
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