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 i...[ Read more ]

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.