title: Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction.
abstract: 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.
authors.affiliation: Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betzenhauser
authors.forename: Steve
authors.initials: S
authors.lastname: Reiken
authors.forename: Albano C
authors.initials: AC
authors.lastname: Meli
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xie
authors.forename: Bi-Xing
authors.initials: BX
authors.lastname: Chen
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003072:Cognition Disorders / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D040921:Stress Disorders, Traumatic / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium