The role of glutamate transporters and the scaffolding protein IQGAP1 in the regulation of AMPA receptor trafficking and turnover
Jarzylo, Larissa A.
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Alterations in the strength of glutamatergic synaptic activity shape the synaptic localization of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs), and this process is thought to underlie higher brain functions such as learning and memory. During excitatory synaptic transmission, the presynaptic neuron releases glutamate which activates AMPARs that, in turn, conduct postsynaptic synaptic transmission. Concomitantly, excitatory amino acid transporters (EAATs) re-uptake released glutamate, thereby curtailing the strength of AMPAR synaptic activation. Although the coordination of glutamate receptors and transporters likely occurs, whether and how transporter activity affects AMPAR synaptic expression remains less clear. Using cultured hippocampal neurons, I show that inhibition of glutamate transporters leads to a rapid redistribution and dramatic reduction in AMPAR synaptic accumulation. I also find that EAAT inactivity causes AMPAR internalization and reduction of surface AMPAR expression. AMPAR reduction can be blocked by suppression of proteasome activity and results in the induction of receptor ubiquitination, strongly indicating the involvement of proteasome-mediated receptor degradation. In searching for the molecular components involved in activity-induced receptor endocytosis, I identified the molecular scaffold, IQGAP1. IQGAP1 enhances AMPAR turnover through binding to ubiquitinated AMPARs and promoting receptor internalization. In addition, I also found a decrease in AMPAR abundance following enhanced expression of IQGAP1. Furthermore, activation of parasynaptically localized NR2B-containing NMDA receptors (NMDARs) is required for AMPAR degradation, suggesting glutamate spillover from the synaptic cleft occurs during EAAT inhibition. Interestingly, I found that the neuronal, but not the glial glutamate transporters are responsible for the observed AMPAR regulation. Thus, my results strongly indicate a role for neuron-specific glutamate transporters in the regulation of AMPAR trafficking and synaptic stability. Since aberrant neuronal glutamate transporter function has been implicated in a number of neurological conditions and diseases, it will be interesting to explore changes how alterations in AMPAR expression during transporter dysfunction affects the development of these pathologies.
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