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    Elucidating the Molecular Pathway through which L-Lactate potentiates NMDAR Signaling

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    Name:
    Hanan Mahmood Dissertation.pdf
    Size:
    15.97Mb
    Format:
    PDF
    Description:
    PhD Dissertation
    Embargo End Date:
    2021-05-26
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    Type
    Dissertation
    Authors
    Mahmood, Hanan S. cc
    Advisors
    Magistretti, Pierre J. cc
    Committee members
    Gojobori, Takashi cc
    Moran, Xose Anxelu G. cc
    Martin, Jean-Luc
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2019-06
    Embargo End Date
    2021-05-26
    Permanent link to this record
    http://hdl.handle.net/10754/660266
    
    Metadata
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    Access Restrictions
    At the time of archiving, the student author of this dissertation opted to temporarily restrict access to it. The full text of this dissertation will become available to the public after the expiration of the embargo on 2021-05-26.
    Abstract
    The role of L-Lactate has expanded from an energy metabolite to a signaling molecule in neurons. Studies have shown that L-Lactate plays a role in neuroprotection and in NMDAR-dependent long-term memory formation. The aim of this dissertation is to characterize the role of L-Lactate as a signaling molecule and understand the molecular mechanism through which L-Lactate potentiates NMDAR signal. Using mass spectrometry, I monitored the time-dependent changes in the phosphoproteome of cortical neuronal cultures in response to Lactate. The phosphoproteomic analysis highlighted a number of cytoskeletal proteins involved in synapse remodeling as well as axon guidance that were regulated by L-Lactate. In addition, I found that L-Lactate induced phosphorylation of proteins involved in the MAPK pathway, as reported in an earlier study. I hypothesize the involvement of CaMKII in this mechanism. CaMKII is one of the most abundant kinases in the brain and plays a role in learning and memory via interaction with NMDAR. Using CaMKII inhibitors and mutants of the NMDAR subunit GluN2B, the findings in this dissertation provide evidence for the involvement of CaMKII, specifically, the interaction between CaMKIIa and GluN2B, as a requirement for the L-Lactate mediated potentiation of NMDAR signal. In addition, to gain insight into the evolution of lactate from a metabolite to a signaling molecule, this study explores the evolution of glutamate as a signaling molecule in multicellular organisms so it may serve as a model for evolution of metabolites like lactate into signaling molecules. For this purpose, the model organism Hydra was used, since it belongs to phylum Cnidaria, evolutionarily one of the first phyla to have a nervous system. In order to explore whether glutamate receptors, particularly, NMDAR are functionally expressed in Hydra and are localized in neurons, a line of transgenic Hydra expressing a calcium indicator (GCaMP6s) in neurons was generated. With the transgenic Hydra line, I attempted to measure the in vivo response of neurons in Hydra to glutamate. This study highlights several ground work experiments with an extensive discussion of implications and challenges and an outlook for future investigations.
    Citation
    Mahmood, H. S. (2019). Elucidating the Molecular Pathway through which L-Lactate potentiates NMDAR Signaling. KAUST Research Repository. https://doi.org/10.25781/KAUST-KGH02
    DOI
    10.25781/KAUST-KGH02
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-KGH02
    Scopus Count
    Collections
    Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Dissertations

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