Activity-dependent post-translational regulation of palmitoylating and de-palmitoylating enzymes in the hippocampus

Abstract

Activity-induced changes in protein palmitoylation can regulate the plasticity of synaptic connections, critically impacting learning and memory. Palmitoylation is a reversible post-translational modification regulated by both palmitoyl-acyl transferases that mediate palmitoylation and palmitoyl thioesterases that depalmitoylate proteins. However, it is not clear how fluctuations in synaptic activity can mediate the dynamic palmitoylation of neuronal proteins. Using primary hippocampal cultures, we demonstrate that synaptic activity does not impact the transcription of palmitoylating / depalmitoylating enzymes, changes in thioesterase activity, nor post-translational modification of the depalmitoylating enzymes, ABHD17 and APT2. In contrast, synaptic activity does mediate post-translational modification of the palmitoylating enzymes ZDHHC2, ZDHHC5, and ZDHHC9 (but not ZDHHC8) to influence protein-protein interaction, enzyme stability and enzyme function. Post-translational modifications of ZDHHC enzymes were also observed in the hippocampus following fear conditioning. Together, our findings demonstrate that signaling events activated by synaptic activity largely impact activity of the ZDHHC family of palmitoyl-acyl transferases with less influence on the activity of palmitoyl thioesterases.