S-nitrosylation of GRK regulates dopaminergic signaling and contributes to L-dopa induced dyskinesia in Parkinson's disease

Abstract

G-protein coupled receptor kinase (GRK) is a family of proteins that can phosphorylate and subsequently desensitize various agonist activated G-protein coupled receptor signaling upon agonist activation. S-nitrosylation is emerging as an important post-transcriptional modification that regulates the function of a wide range of signaling molecules. Recent studies show that nitric oxide (NO) down- regulates GRK2 activity; however, the molecular mechanism behind for how NO regulates GRK4 sub-family signaling is still not known. In this study, we demonstrated that S-nitrosylation of GRK6 on Cys 474 dramatically increases its kinase activity and promotes dopamine receptors internalization. More importantly, the level of GRK6 S-nitrosylation is dysregulated in a mice model of L-Dopa induced dyskinesia. It is well documented that nitrosative stress and dopaminergic signaling are involved in the onset and progress of Parkinson’s disease (PD). Our study reveals a potential molecular mechanism through which NO can affect dopaminergic neuronal signaling and contribute to PD.

Date of Award	2014
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology