Dynamics of postsynaptic glutamate receptor targeting
Introduction
Glutamate is the main excitatory neurotransmitter in the mammalian brain. Glutamate receptors are classified into two main categories: ligand-gated ion channels (ionotropic receptors) and G-protein-coupled receptors (metabotropic receptors). Among the different types of ionotropic glutamate receptor, the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA)-type and the kainate-type receptors mediate most fast synaptic transmission in the mammalian brain, whereas the N-methyl-d-aspartate (NMDA)-type receptor mediates a slower component of synaptic transmission that is important for modulating synaptic function. Metabotropic glutamate receptors (mGluRs) are categorized into three groups on the basis of both their pharmacological profiles and the second messenger systems to which they are coupled. Group I mGluRs (mGluR1 and mGluR5) are predominantly localized at the postsynaptic sites, whereas others mGluRs function at presynaptic sites.
Ionotropic glutamate receptors are primarily targeted to neuronal dendrites, although increasing evidence suggests that all three types of ionotropic glutamate receptor can be targeted to presynaptic membranes in a neuron-specific and sometimes subunit-specific manner [1, 2, 3, 4, 5, 6]. Like many proteins, glutamate receptors are synthesized in the endoplasmic reticulum and transported to the Golgi apparatus. Neurons are highly polarized cells in which proteins are sorted and transported to their target locations after exiting from the Golgi. Many pathways and mechanisms are involved in synaptic targeting of glutamate receptors.
In this review, we focus mainly on targeting of glutamate receptors to neuronal dendrites, summarizing recent findings on receptor dynamics related to the surface and synaptic localization of these receptors.
Section snippets
Vesicular trafficking versus lateral diffusion in dendrites
Several mechanisms, such as microtubule-based vesicular transport and lateral diffusion in the plasma membrane, might be involved in localizing glutamate receptors to dendritic membranes (Figure 1).
Vesicles containing NMDA receptors (NMDARs) are associated with microtubules in dendrites, and a specific kinesin motor KIF17 is required for trafficking NMDAR-containing vesicles [7, 8]. Mobile NMDARs are also present at the plasma membrane [9, 10], however, suggesting that lateral diffusion in the
Lateral movement into and out of synapses
Glutamate receptors in dendritically sorted vesicles are inserted into the cytoplasmic membrane, most probably at extrasynaptic sites because of the spatial obstruction presented by the dense protein network in the postsynaptic density (Figure 1). A two-step trafficking model for AMPARs, involving membrane insertion followed by synaptic recruitment, has been proposed by a study of Stargazin-deficient neurons [45]. Evidence supporting the notion that extrasynaptic receptors act as a reservoir
Fast incorporation of locally translated glutamate receptors
Since the initial observation of protein synthetic machinery in neuronal dendrites [58], local translation of protein has emerged as an attractive mechanism that contributes both to synaptogenesis and to long-lasting changes in synaptic efficacy (recently reviewed in [59, 60]). Glutamate receptor mRNAs are sorted to dendrites, and this sorting might be regulated by changes in synaptic activity [61, 62••]. Exciting progress has been made in recent years in understanding activity-dependent
Conclusions
Synaptic incorporation of glutamate receptors is one of the most important steps in synaptogenesis. The conventional view that the AMPAR is the most dynamic component of the excitatory synapse has been challenged by recent observations of equally dynamic movements of NMDARs and mGluRs into and out of synapses. In addition to regulating receptor trafficking, both synaptic activity and the cytoskeleton network influence the rapid turnover and lateral movement of postsynaptic scaffolds at active
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Roger Nicoll and members of the Chen laboratory for discussions and comments on the manuscript. LC is supported by grants from the Arnold and Mabel Beckman Foundation, the David and Lucile Packard Foundation, the WM Keck Foundation, National Alliance for Research on Schizephrenia and Depression (NARSAD) and the National Institute of Mental Health (NIMH).
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