REGULATION OF SIGNALING BY MGLUR5

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DESCRIPTION(Adapted from applicant's abstract): The hippocampus is a limbic cortical structure that plays an important role in learning and memory, and is a primary site of temporal lobe epilepsy and Alzheimer's disease. Glutamate is the primary neurotransmitter at excitatory synapses in the hippocampus, where it acts on both ionotropic and metabotropic glutamate receptors (mGluRs). Particular attention has been focused on the NMDA subtype of glutamate receptor because of its unique role in certain forms of learning, memory, and pathological conditions including epileptic responses and excitotoxicity. Interestingly, recent studies reveal that activation of one mGluR subtype, mGluR5, can dramatically potentiate currents through NMDA receptor channels in hippocampal neurons. Furthermore, low concentrations of NMDA potentiate responses to mGluR5 activation. This positive feedback regulation between mGluR5 and NMDA receptors could play a critical role in signal amplification and may be important for NMDA receptor function. Consistent with this, several previous studies suggest that mGluR5 plays an important role in several receptor-dependent forms of synaptic plasticity and could contribute to pathological responses to NMDA receptor activation. Previous studies reveal that mGluR5 is desensitized by activation of protein kinase C (PKC) which directly phosphorylates the receptor. We recently found that mild activation of NMDA receptors-with low concentrations of NMDA-potentiates mGluR5-mediated responses by reversing this agonist-induced desensitization. Interestingly, stronger activation of NMDA receptors reduced mGluR5-mediated responses and increased mGluR5 phosphorylation. This is especially interesting in light of recent studies that suggest that low frequency stimulation of glutamatergic afferents to hippocampal area CA1 induces preferential activation of the protein phosphatase calcineuron whereas high frequency stimulation leads to activation of PKC and a net increase in protein phosphorylation. Based on this and a number of other previous studies, we postulated that the differential effects of different concentrations of NMDA on mGluR5 are mediated by net increases and decreases in mGluR5 phosphorylation. Furthermore, we postulate that low frequency stimulation of glutamatergic afferents induces preferential dephosphorylation of mGluR5 and potentiates mGluR5-mediated responses whereas high frequency stimulation induces a net increase in mGluR5 phosphorylation and inhibition of mGluR5-mediated responses. A combination of molecular, biochemical and electrophysiological techniques will be used to directly test these hypotheses.