Reactive oxygen species (ROS) is considered as one of the main factors inducing physiological aging. However, molecular mechanisms how ROS induce physiological and pathological aging have not been fully understood.
In the cerebellar parallel fiber (PF)-to-Purkinje cell (PC) synapse (PF synapse), nitric oxide (NO)-dependent long-term potentiation (PF-LTP) is characterized. Previous studies indicated that the PF-LTP is dependent on S-nitrosylation of type I ryanodine receptor (RyR1), an intracellular Ca²⁺-release channel, and the resulting novel type of Ca²⁺-release, nitric oxide-induced Ca²⁺-release (NICR) in cerebellar PCs.
Thiol groups in cysteine residue are the target of S-nitrosylation of proteins by NO as well as the target of disulfidation (disulfide-bond formation) by ROS. Thus, it is highly possible that protein disulfidation blocks the induction of S-nitrosylation and the resulting S-nitrosylation-dependent biological events, such as PF-LTP.
In this symposium, I will introduce our recent studies designated to test this hypothesis. In the cerebellar slices pretreated with ROS, S-nitrosylation of RyR1, NICR and PF-LTP were impaired. Furthermore, in the cerebellar slices from aged mice (about 2-years old), RyR1 S-nitrosylation, NICR and PF-LTP were again inhibited. These results support the hypothesis, and also suggest that endogenous ROS possibly induce physiological aging through the inhibition of S-nitrosylation in old animals.