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    The role of L-lactate in NMDAR-CaMKIIα Interaction

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    Type
    Thesis
    Authors
    Alamoudi, Rayyan T. cc
    Advisors
    Magistretti, Pierre J. cc
    Committee members
    Fiumelli, Hubert cc
    Liberale, Carlo cc
    Daffonchio, Daniele cc
    Program
    Bioscience
    KAUST Department
    Biological and Environmental Sciences and Engineering (BESE) Division
    Date
    2019-06
    Permanent link to this record
    http://hdl.handle.net/10754/655940
    
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    Abstract
    NMDA receptors are the most studied receptors in the field of neuroscience and are known to play an important role in development and plasticity. These receptors exhibit different kinetics depending on their subunit composition. NR2A and NR2B are the predominating NMDAR subunits in the brain. These receptors localize to synapses where they interact with other proteins including CaMKIIα, an abundant kinase which plays an important role in synaptic plasticity. Although CaMKIIα is known to bind to all types of NMDARs, it exhibits a higher affinity to NR2B compared to NR2A subunits. Studies have shown that lactate acts as a signaling molecule promoting the expression of genes related to synaptic plasticity via NMDARs activation. However, the mechanism describing how lactate exerts these effects is not well understood. We hypothesize that the redox state change, resulting from the metabolic conversion of lactate to pyruvate, may promote the interaction between CaMKIIα and NMDARs, thereby potentiating NMDARs activity. To tackle this question, we used a pharmacogenetics model consisting of NMDARs expressing HEK293 cells in the presence or absence of CaMKIIα. To monitor NMDARs activity, we use the ratio-metric calcium dye Fura-2 in calcium imaging experiments. We report that L-lactate decreases the peak responses of the NR2A and NR2B NMDARs in the absence of CaMKII expression. Upon CaMKII presence, we found that lactate prolongs the activation period of GluN2B as observed during the washout period and modestly increase the peak response of GluN2A NMDARs. Interestingly, we confirm that expressing CaMKIIα in control (no lactate) HEK cells significantly augmented NR2B but not NR2A NMDARs. We also report that pyruvate was able to increase peak responses of both NR2A and NR2B NMDARs in the absence of CaMKII, while it only increased the NR2A-NMDAR peak responses in the presence of CaMKII. These results suggest that lactate exerts a neuroprotective effect in the absence of CaMKII and it slightly boosts NR2B NMDARs activity when CaMKII is expressed, possibly favoring plasticity. Moreover, data obtained with pyruvate indicates that in our HEK cell model pyruvate affects the NMDARs in a manner independent of the presence of CaMKII through an alternative mechanism.
    Citation
    Alamoudi, R. T. (2019). The role of L-lactate in NMDAR-CaMKIIα Interaction. KAUST Research Repository. https://doi.org/10.25781/KAUST-R8CX0
    DOI
    10.25781/KAUST-R8CX0
    ae974a485f413a2113503eed53cd6c53
    10.25781/KAUST-R8CX0
    Scopus Count
    Collections
    Biological and Environmental Sciences and Engineering (BESE) Division; Bioscience Program; Theses

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