Role of leaky neuronal ryanodine receptors in stress-induced cognitive dysfunction

Cell. 2012 Aug 31;150(5):1055-67. doi: 10.1016/j.cell.2012.06.052.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cognition Disorders / metabolism*
  • Hippocampus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Stress Disorders, Traumatic / metabolism


  • Ryanodine Receptor Calcium Release Channel
  • Calcium