Abstract
The molecular mechanisms underlying plastic changes in the strength and connectivity of excitatory synapses have been studied extensively for the past few decades and remain the most attractive cellular models of learning and memory. One of the major mechanisms that regulate synaptic plasticity is the dynamic adjustment of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor content on the neuronal plasma membrane. The expression of surface AMPA receptors (AMPARs) is controlled by the delicate balance between the biosynthesis, dendritic transport, exocytosis, endocytosis, recycling and degradation of the receptors. These processes are dynamically regulated by AMPAR interacting proteins as well as by various post-translational modifications that occur on their cytoplasmic domains. In the last few years, protein ubiquitination has emerged as a major regulator of AMPAR intracellular trafficking. Dysregulation of AMPAR ubiquitination has also been implicated in the pathophysiology of Alzheimer’s disease. Here we review recent advances in the field and provide insights into the role of protein ubiquitination in regulating AMPAR membrane trafficking and function. We also discuss how aberrant ubiquitination of AMPARs contributes to the pathogenesis of various neurological disorders, including Alzheimer’s disease, chronic stress and epilepsy.
Highlights
The binding of glutamate to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) mediates the fast, moment-to-moment transmission of excitatory signals in the mammalian central nervous system
Studies that emerged in the last few years have demonstrated an important function of the ubiquitin signaling pathway in regulating AMPA receptors (AMPARs) trafficking and function, this field of research is still in its infancy
Studies of AMPAR ubiquitination in heterologous systems, such as those performed in HEK293 cells, are not ideal and must be interpreted with caution
Summary
The binding of glutamate to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) mediates the fast, moment-to-moment transmission of excitatory signals in the mammalian central nervous system. Dynamic trafficking of AMPARs is one of the major mechanisms underpinning various forms of synaptic plasticity, including Hebbian and homeostatic plasticity (Pozo and Goda, 2010; Huganir and Nicoll, 2013) These processes are tightly regulated by the orchestrated binding of AMPAR binding proteins, as well as by reversible post-translational modifications that occur on the carboxyl terminal domains of AMPAR subunits (Anggono and Huganir, 2012; Lu and Roche, 2012). The activity of NMDARs plays an important role in modulating the ubiquitination of AMPARs induced by bicuculline (Lussier et al, 2011; Widagdo et al, 2015) These findings suggest that AMPA and bicuculline stimulate two molecularly distinct signaling pathways, which may result in the recruitment of different E3 ligases and dictate the routes of AMPAR trafficking and subsequent degradation through the lysosomal or proteasomal pathways
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