Kainate receptor trafficking: physiological roles and molecular mechanisms

Isaac, John T.R.; Mellor, Jack R.; Hurtado, David; Roche, Katherine W.

doi:10.1016/j.pharmthera.2004.08.006

Cited by 39 publications

(43 citation statements)

References 74 publications

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“…However, we find that when this mutation (862-RRRRR-866) is introduced in the context of full-length KA2, these mutations have very little effect on ERretention. All previously identified trafficking motifs that regulate glutamate receptor localization are contained within the cytosolic C-terminal domains of glutamate receptor subunits (Wenthold et al, 2003;Isaac et al, 2004;Vandenberghe and Bredt, 2004;Jaskolski et al, 2005). In contrast, our studies reveal a novel RxR motif (580-RAR-582) within an intracellular loop of KA2, a region previously overlooked in receptor trafficking of kainate receptors and other glutamate receptor subtypes.…”

Section: Discussioncontrasting

confidence: 48%

“…Kainate receptors are widely distributed throughout the brain at both presynaptic and postsynaptic sites (Lerma, 2003;Isaac et al, 2004), where they modulate neurotransmitter release or mediate excitatory neurotransmission, respectively. Kainate receptors exist as both homomeric and heteromeric complexes, with subunit composition affecting the pharmacological and physiological properties of the receptors.…”

Section: Introductionmentioning

confidence: 99%

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Identification of an Endoplasmic Reticulum-Retention Motif in an Intracellular Loop of the Kainate Receptor Subunit KA2

et al. 2006

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Neuronal kainate receptors are typically heteromeric complexes composed of GluR5-7 and KA1-2 subunits. Although GluR5-7 can exist as functional homomeric channels, the KA subunits cannot. KA2 is widely expressed in the CNS, and KA2/GluR6 heteromers are the most prevalent subunit composition in brain. Previous work has identified endoplasmic reticulum (ER)-retention motifs in the C terminus of KA2, which prevent surface expression of KA2 homomers. However, we find that, when these motifs are mutated, only a small fraction of KA2 is surface expressed. We now identify an additional ER retention motif in the intracellular loop region of KA2, which, when mutated together with the C-terminal motifs, significantly increases the level of KA2 surface expression. However, electrophysiological analysis of surface-expressed KA2 homomers indicates that they do not form functional ion channels. In heterologous cells, a large fraction of KA2 remains intracellular even when the trafficking motifs are mutated or when GluR6 is coexpressed. Therefore, we analyzed the trafficking of endogenous KA2 in vivo. We find that native KA2 surface expression is dramatically reduced in GluR6 knock-out mice compared with wild-type mice. In contrast, KA2 trafficking was unaffected in the GluR5 knock-out. Thus, our study demonstrates that trafficking motifs in both the intracellular loop and C terminus regulate KA2 surface expression; however, in neurons, GluR6 oligomerization is required for egress of KA2 from the ER and transport to the cell surface. The combination of these mechanisms likely prevents surface expression of nonfunctional KA2 homomers and ensures a high level of GluR6/KA2 heteromeric kainate receptors.

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Section: Discussioncontrasting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Identification of an Endoplasmic Reticulum-Retention Motif in an Intracellular Loop of the Kainate Receptor Subunit KA2

et al. 2006

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“…[14][15][16] Reduced Q/R editing of GluK2 results in increased calcium permeability and altered I/V relations. 17 Thus, KARs comprise a diverse combination of subunits and subunit isoforms that are subject to different sets of protein interactions leading to differential trafficking and surface expression, thereby influencing the fate and function of the receptors in which they assemble [3][4][5]7,8 ( Figure 2). …”

Section: Advanced Reviewmentioning

confidence: 99%

“…8 However, electrophysiology and pharmacology can be difficult to interpret even in well-characterized cell types and the precise location and composition of KARs at some synapses has not been fully established. [3][4][5]8 Synaptic electrophysiological studies have identified presynaptic roles for KARs in several brain regions. Further, early [ 3 H]kainate-binding studies in the rat hippocampus suggested the existence of presynaptic KARs on mossy fiber terminals.…”

Section: Roles and Distribution Of Kars Localizationmentioning

confidence: 99%

“…Expression of KAR subunit mRNAs 19 and proteins [2][3][4][5] are tightly developmentally regulated and KARs play important roles in developmental plasticity. Interestingly, KAR activation has different effects during different phases of development; in immature rat hippocampal slices KAR activation enhances axonal motility, whereas in mature slices, KAR activation inhibits motility.…”

Section: Developmental Rolesmentioning

confidence: 99%

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Kainate receptor trafficking

González‐González

Konopacki

Rocca

et al. 2011

WIREs Membr Transp Signal

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Kainate receptors (KARs) are ligand-gated ion channels that can regulate neuronal network activity and are involved in processes ranging from neuronal development and differentiation to neurodegeneration and neuronal cell death. They are tetrameric assemblies which can comprise different subunit combinations and are differentially targeted to specific cell surface compartments including preand postsynaptic membranes where they perform distinct functional roles. The processes regulating the constitutive and activity-dependent trafficking of KARs are subtle and complex. Intricate combinations of protein-protein interactions and post-translational modifications orchestrate their surface membrane delivery, residence time, internalization, and recycling or degradation. Furthermore, in addition to regulating surface expression, interacting proteins connect receptors to anchoring and signaling pathways. Although our knowledge of the processes that regulate KAR trafficking is far from complete, there has been significant progress toward defining the roles of many of these protein partners and post-translational modifications. 

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Biochemical Fractionation of Brain Tissue for Studies of Receptor Distribution and Trafficking

et al. 2008

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An important tool for studying the regulation of synapses is a rapid and reliable means of separating synaptic and intracellular proteins. This unit presents a technique for analysis of brain tissue which relies on differential centrifugation to separate proteins present at synaptic sites from those found in intracellular cytoplasmic and vesicular pools. The method is efficient in that only small amounts of tissue, such as might be obtained from a small region of a rodent brain, are required. It is reproducible and, in conjunction with immunoblot or immunoprecipitation techniques, can produce reliable quantitative data. The protocol will be of interest to those conducting a variety of different studies related to the localization and trafficking of brain receptors and signaling molecules.

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Kainate receptor trafficking: physiological roles and molecular mechanisms

Cited by 39 publications

References 74 publications

Identification of an Endoplasmic Reticulum-Retention Motif in an Intracellular Loop of the Kainate Receptor Subunit KA2

Identification of an Endoplasmic Reticulum-Retention Motif in an Intracellular Loop of the Kainate Receptor Subunit KA2

Kainate receptor trafficking

Biochemical Fractionation of Brain Tissue for Studies of Receptor Distribution and Trafficking

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