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Overview of the Lab
The research focus of the Laboratory of Molecular Signaling (LMS) is to elucidate mechanisms of omega-3 fatty acids, especially docosahexaenoic acid (DHA, 22:6n-3) in neuronal development and function with particular reference to the modulation by ethanol. We investigate biochemical mechanisms by which omega-3 fatty acids and ethanol modify neuronal cell membrane structure, and characterize consequential molecular and cellular signaling involved in neuronal survival and differentiation. We also investigate the metabolism of polyunsaturated lipids to bioactive mediators and their in vivo implication in neurodevelopment and neuroprotection. To this end, we devise multidisciplinary approaches using molecular, cellular and modern instrumental techniques as well as animal models. The current research topics include 1) neurogenesis, neuritogenesis, synaptogenesis and neuroinflammation affected by DHA and DHA metabolites; 2) identification of target receptors of active DHA-metabolites; 3) molecular mechanisms by which DHA and ethanol influence Akt activation and neuronal survival; 4) development of modern mass spectrometric techniques to characterize protein-protein and protein-membrane interactions and protein conformation; and 5) in vivo evaluation of neuroprotective effects of DHA, bioactive DHA metabolites and their synthetic analogues using brain injury models.
The Laboratory conducts a range of studies related to the metabolism and effects of docohexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid. DHA promotes the accumulation of phosphatidylserine (PS), which prevents neuronal cell death. Conversely, dietary deficiencies and long term ethanol exposure both deplete PS from neuronal membranes and accelerate apoptosis. The Laboratory is interested in the structure and function of Akt, a protein that mediates DHA’s antiapoptotic effects. The Laboratory has found that Akt undergoes significant conformational changes at each step in the activation process, and it has identified the protein’s phosphorylation domains. In particular, the serine residue at position 473 (S473) is an important phosphorylation site for Akt activation. The Laboratory has conducted high-throughput screening of molecular libraries to identify compounds that interact with S473, in the hope of developing therapies that promote neuronal longevity. Additionally, the laboratory has examined docosahexaenoylethanolamide (DEA), a metabolite of DHA, and it has found that DEA promotes neurite development, synaptogenesis and glutamate receptor expression in murine hippocampal neurons. Conversely, feeding mice DHA-deficient diets inhibits neurite development in the hippocampus. The Laboratory’s work also suggests that DHA plays an important role in expression of a number of plasma membrane proteins, and that DHA-related upregulation of PS is specific to neuronal cells. Finally,the Laboratory has found that ethanol exposure decreased the salsolinol levels in the striatum and nucleus accumbens of alcohol-preferring rats. This is an unexpected result, because salsolinol is considered a potential biomarker for alcoholism.
Lee JW, Huang BX, Kwon H, Rashid MA, Kharebava G, Desai A, Patnaik S, Marugan J, Kim HY. Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function. Nat Commun. 2016;7:13123.
Park T, Chen H, Kim HY. GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine. J Neuroinflammation. 2019;16(1):225.
Huang BX, Hu X, Kwon HS, Fu C, Lee JW, Southall N, Marugan J, Kim HY. Synaptamide activates the adhesion GPCR GPR110 (ADGRF1) through GAIN domain binding. Commun Biol. 2020;3(1):109.
Kim HY, Spector AA. N-Docosahexaenoylethanolamine: A neurotrophic and neuroprotective metabolite of docosahexaenoic acid. Mol Aspects Med. 2018;64:34-44.
Huang BX, Newcomer K, Kevala K, Barnaeva E, Zheng W, Hu X, Patnaik S, Southall N, Marugan J, Ferrer M, Kim HY. Identification of 4-phenylquinolin-2(1H)-one as a specific allosteric inhibitor of Akt. Sci Rep. 2017;7(1):11673.