The Role of mGlu1/5 Signaling and Fragile X Mental Retardation Protein for Cell Surface Expression of the potassium channel Kv4.2 Open Access

Moaven, Aurasch Hassan (2012)

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The Role of mGlu1/5 Signaling and Fragile X Mental Retardation Protein for Cell Surface
Expression of the potassium channel Kv4.2
Patients with fragile X syndrome (FXS), the most common inherited form of intellectual disability, frequently suffer from epileptic seizures. The higher susceptibility to seizure development is recapitulated in Fmr1 Knockout (KO) mice, a mouse model for FXS, but the underlying molecular mechanisms are unknown. The Bassell lab has shown previously that total and cell surface levels of the potassium channel Kv4.2, a major regulator of neuronal excitability, are decreased in the brains of Fmr1 KO mice. Of note, a mutation in Kv4.2 leads to temporal lobe epilepsy in human patients. Therefore, we hypothesize that the decreased levels of total and cell surface Kv4.2 in hippocampal neurons of Fmr1 KO mice may contribute to the
epileptic phenotype. Previous studies have shown that signaling through metabotropic glutamate receptors 1/5 (mGlu1/5) is dysregulated in Fmr1 KO mice, and that antagonists of mGlu5 rescue the seizure phenotype in Fmr1 KO mice and partially restore Kv4.2 cell surface levels. The purpose of this research was to determine how mGlu1/5 signaling regulates the potassium channel Kv4.2 by analyzing endogenous Kv4.2 cell surface expression in mouse hippocampus, and by using a pH sensitive fluorescence reporter protein to quantify Kv4.2 cell surface levels in cultured cell lines. Our study suggests that signaling through mGlu1/5 negatively regulates Kv4.2 cell surface levels. Furthermore, we show that transient siRNA mediated reduction of FMRP is sufficient to decrease Kv4.2 cell surface expression. This thesis motivates further research using the pH sensitive reporter protein in fixed or live cells to study the efficiency of mGlu1/5 downstream signaling antagonists to restore Kv4.2 cell surface levels in the absence of FMRP. In the future, this may help to design therapies to treat seizures in FXS.

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