TOP ＞ Lecture by the Recipient of the 2017 Award for Distinguished Investigator of JSN

Lecture by the Recipient of the 2017 Award for Distinguished Investigator of JSN Study on the phosphorylation signals regulating brain functions 1L2 Study on the phosphorylation signals regulating brain functions Taku Nagai Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine Memory and emotion are essential brain functions through our life. Distinctive neuronal nuclei and networks which responsible for the neuropsychological domains have been identified. It is well known that the prefrontal cortex (PFC), hippocampus and striatum play an important role in memory formation and motivation. Biological system is maintained by ingenious sensing and controlling inside and outside environment of the cells. Protein phosphorylation is one of the key process to lead neuronal activity. Various intracellular signals implicate in neuronal excitability and plasticity through protein kinases including Akt, CDK, MAPK, and PKA. However, the intracellular signals relevant to those brain functions remain largely unknown. In the present study, I investigated the phosphorylation signal regulating brain functions including memory and emotion. I demonstrated that activation of ERK1/2 (also known as MAPK1/3) following the stimulation of dopamine D1 receptors is necessary for the protein synthesis-dependent long-term retention of recognition memory in the PFC (Nagai et al., Learn Mem. 2007). I also found that Girdin plays crucial for memory, and activity-dependent Girdin phosphorylation induced by Akt is crucial for NMDA receptor activation associated with synaptic plasticity in the hippocampus underlying memory formation (Nakai et al., J. Neurosci. 2014; Itoh et al., Rev Neurosci. 2016). Furthermore, neuronal PAS domein 4 (Npas4) has been identified as a responsible gene for stress-induced brain dysfunction, and increased CDK5-dependent phosphorylation of synapsin I (Ibi et al., J. Neurochem. 2008; Yun et al., J. Biol. Chem. 2013). Recently, I developed a phospho-proteomic analysis method to identify known and novel PKA substrates downstream of the D1R and obtained more than one hundred candidate substrates, including Rap1 GEF (Rasgrp2). PKA-mediated Rasgrp2 phosphorylation enhances its GEF activity on Rap1. Rap1 activated by PKA-Rasgrp2 regulates neuronal excitability and cocaine reward-related behavior via MAPK1/3 (Nagai et al., Neuron 2016; Nagai et al., Trend Pharmacol. Sci. 2016). These results indicate that the phosphorylation signals regulate memory and emotion through the changes in neuronal excitability and plasticity of neurons. The findings promote molecular-level understanding of neuropsychological diseases by elucidating the brain function.