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Objective Precise regulation of cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for the proper neuronal development and functions.Cdk5 is activated through its association with the neuron-specific activator p35 or p39.Nonetheless, how its kinase activity is regulated in neurons is not well understood.In the present study, we investigate whether Cdk5 is regulated by the S-nitrosylation, a post-translational modification of protein, and how the S-nitrosylation of Cdk5 modulates its kinase activity and functions during neuronal development.Methods The kinase activity of Cdk5 upon S-nitrosylation was measured using in vitro kinase assay.The potential physiological role of S-nitrosylation of Cdk5 in neuronal development was studied by overexpressing Cdk5 or its C83A mutant in hippocampal neurons.The change in the neuronal morphology was examined using confocal microscopy.Results (1) Cdk5 is S-nitrosylated both in vitro and in vivo.(2) S-nitrosylation of Cdk5 inhibits its kinase activity.(3) Inhibition of the S-nitrosylation of Cdk5 enhances dendrite growth in neurons.Conclusion S-nitrosylation of Cdk5 regulates its activity and dendritic development.