LiLian Yuan of Des Moines University will present a lecture entitled: Identification of Novel Antidepressant Mechanism of Ketamine by Kinome Profiling.
Abstract: Ketamine at sub-anesthetic doses has shown promising results as a potent and fast-acting antidepressant. Evidence from animal model studies suggests that the functional restoration by ketamine is associated with activation of MAPK and mTOR signaling cascades in the prefrontal cortex (PFC) within a few hours of ketamine administration, followed by a second wave of synaptic protein upregulation. Together, these molecular events lead to rapid synaptogenesis and reversal of neural atrophy. Furthermore, (2R, 6R)-hydroxynorketamine (HNK) has recently been identified as the main active component of ketamine metabolism. HNK is believed to be responsible for the antidepressant actions of ketamine, but with minimal side effects, providing a distinct tool to examine mechanisms of ketamine’s action. Although some kinases and related pathways have been implicated in both depression pathophysiology and ketamine treatment, there has not been a systematic, proteomics analysis of the kinome or the molecular mechanisms of ketamine action, to provide insight into its mechanism of action as an antidepressant. To fulfill this critical need, we performed a comprehensive brain kinome profile (and characterization of related substrates) through a unique, unbiased proteomic screening method to uncover novel targets of ketamine antidepressant signaling. This high-throughput screening is expected to provide information on the effects of three major factors on the kinome activity profile of PFC: 1) stress; 2) sex; 3) antidepressant treatment (ketamine or HNK). A better understanding of the kinase landscape will provide mechanistic insight into how ketamine promotes its rapid antidepressant effects.
NIH grant MH108043