The regulation of glutamate receptor trafficking and function by TARPs and other transmembrane auxiliary subunits

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At excitatory synapses in the brain, glutamate released from nerve terminals binds to glutamate receptors to mediate signaling between neurons. Glutamate receptors expressed in heterologous cells show ion channel activity. Recently, native glutamate receptors were shown to contain auxiliary subunits that modulate the trafficking and/or channel properties. The AMPA receptor (AMPAR) can contain TARP and CNIHs as the auxiliary subunits, whereas kainate receptor (KAR) can contain the Neto auxiliary subunit. Each of these auxiliary subunits uniquely modulates the glutamate receptors, and determines properties of native glutamate receptors. A thorough elucidation of the properties of native glutamate receptor complexes is indispensable for the understanding of the molecular machinery that regulates glutamate receptors and excitatory synaptic transmission in the brain.

Highlights

► Native glutamate receptors contain pore subunits and auxiliary subunits. ► Different glutamate receptors bind to distinct auxiliary subunits. ► Auxiliary subunits modulate trafficking and/or channel properties. ► Each of the auxiliary subunits uniquely modulates glutamate receptors.

Introduction

Neurons connect with each other physically and functionally to form neuronal circuits. Neurons communicate mainly at synapses via chemical neurotransmission. The principal excitatory neurotransmitter in the vertebrate brain is glutamate. Glutamate released from presynaptic terminals binds to postsynaptic ionotropic glutamate receptors (iGluRs) to depolarize postsynaptic membranes. The spatial and temporal summation of postsynaptic depolarizations then may generate action potentials in the postsynaptic neuron that transmit information to subsequent neurons in the neuronal circuit. The strength and pattern of synaptic transmission are crucial factors for the proper function of neuronal connections. Synaptic strength is mediated by changes in the concentration of glutamate in the synaptic cleft, as well as by the number and channel properties of glutamate receptors. Thus, it is important to understand the physiological mechanisms that govern glutamate receptor abundance and functional properties at synapses.

Section snippets

Glutamate receptors and auxiliary subunits

Ionotropic glutamate receptors are classified, using pharmacology, into three types: the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, the N-methyl-d-aspartate (NMDA)-, and the kainate (KA)-type [1, 2, 3]. When expressed in heterologous cells, the iGluRs show glutamate-dependent ion channel activity, and their expression alone is sufficient to form a channel pore. However, native iGluRs also contain auxiliary subunits, which modulate the trafficking and/or the channel properties

TARPs and CNIH2/3 regulate AMPAR trafficking and function

At synapses, the number and channel properties of AMPARs must be controlled in basal transmission and regulated upon neuronal activity. The AMPAR auxiliary subunits, TARPs and CNIH2/3, are important for the regulation of AMPAR activity at synapses. CNIH2 and CNIH3, but not CNIH1 or CNIH4, have been shown to bind to AMPARs [7••]. Based upon characteristic features in their modulation of channel properties and/or trafficking of AMPARs, the six TARP isoforms are classified as type 1a

TARPs regulate AMPA receptor numbers at synapses

TARPs stabilize AMPARs at synapses via direct interactions with the post-synaptic density (PSD)-enriched PSD-95 and other MAGUKs (Figure 1) [4, 5, 6, 10, 11, 12]. TARPs can be co-purified with AMPA receptors from the brain [13, 14, 15], and the c-terminal PDZ binding motifs of the TARPs directly interact with the PDZ domains of PSD-95 or other MAGUKs [16, 17]. This interaction was shown to be necessary for synaptic AMPAR function by measuring AMPAR-mediated excitatory post-synaptic currents

TARPs regulate channel properties of AMPA receptors

In addition to the modulation of AMPAR localization, TARPs regulate the channel properties of AMPARs (Figure 2) [4, 5, 6, 10, 11, 12]. The presence of TARPs slows the kinetics of AMPAR deactivation (channel closure upon glutamate removal) and desensitization (channel closure upon glutamate binding) [36, 37, 38]. Stargazer mice (γ-2stg/stg) show no AMPAR activity at cerebellar mossy fiber–granule cell synapses [16], and no miniature EPSCs (mEPSCs) was observed in primary cerebellar granule cell

Roles of CNIH2/3 in regulating AMPA receptors in the brain

CNIH2/3 were identified by proteomic analysis of native AMPAR complexes [7••]. The expression of CNIH2/3 is substantially reduced in the hippocampus of γ-8 KO mice, and the CNIH2/3 protein can be co-immunoprecipitated with AMPARs with the use of an anti-TARP antibody [54••]. These results suggest that CNIH2/3 forms a tripartite complex with AMPAR and γ-8 in the hippocampus, and that γ-8 stabilizes the CNIH/AMPAR complex in this brain region (Figure 1). Although CNIH2 expression enhances the

Roles of Neto auxiliary subunits in KAR function

In comparison with the AMPAR and NMDAR, the KAR exhibits very slow decay kinetics and a distinct distribution revealed by [3H] kainate binding in the brain [61, 62, 63].

The Neto2 protein was identified as an auxiliary subunit of KARs by the biochemical purification of the KAR complex using anti-KAR antibodies from cerebella [64••]. The presence of Neto2 slows the decay kinetics of KARs expressed heterlologously (Figure 2) [64••, 65, 66]. Unlike the modulation of AMPAR trafficking by the TARPs,

Conclusions

The different auxiliary subunits of the iGluRs play distinct roles in their trafficking and function. The TARPs modulate both the trafficking and the channel properties of AMPARs, whereas the Netos and CNIH2/3 modulate the channel properties of KARs and AMPARs, respectively. The identification of novel auxiliary subunits is rapidly expanding out knowledge of the molecular machinery that regulated iGluRs in the brain. However, numerous questions remain unanswered. For example, what roles do

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank members of the Tomita lab for helpful discussions. S.T. is supported by NIH MH077939 and MH085080. C.S. is supported by a Boehringer-Ingelheim Fonds PhD fellowship.

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