Cbln1 Is a Ligand for an Orphan Glutamate Receptor δ2, a Bidirectional Synapse Organizer

Matsuda, Keiko; Miura, Eriko; Miyazaki, Toru; Kakegawa, Wataru; Emi, Kyoichi; Narumi, Shunji; Fukazawa, Yugo; Ito-Ishida, Aya; Kondo, Tetsuro; Shigemoto, Ryuichi; Watanabe, Masahiko; Yuzaki, Michisuke

doi:10.1126/science.1185152

Cited by 325 publications

(347 citation statements)

References 25 publications

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“…5). These findings suggest that C1ql proteins regulate synapses and thus are functionally analogous to cerebellins, which are homologous to C1ql proteins, have a well-documented function in synapse formation, and bind to the orphan glutamate receptor δ2 (39,40).…”

Section: Discussionmentioning

confidence: 97%

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The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

Bolliger¹,

Martinelli²,

Südhof

2011

Proc. Natl. Acad. Sci. U.S.A.

162

168

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C1q-like genes (C1ql1-C1ql4) encode small, secreted proteins that are expressed in differential patterns in the brain but whose receptors and functions remain unknown. BAI3 protein, in contrast, is a member of the cell-adhesion class of G protein-coupled receptors that are expressed at high levels in the brain but whose ligands have thus far escaped identification. Using a biochemical approach, we show that all four C1ql proteins bind to the extracellular thrombospondin-repeat domain of BAI3 with high affinity, and that this binding is mediated by the globular C1q domains of the C1ql proteins. Moreover, we demonstrate that addition of submicromolar concentrations of C1ql proteins to cultured neurons causes a significant decrease in synapse density, and that this decrease was prevented by simultaneous addition of the thrombospondin-repeat fragment of BAI3, which binds to C1ql proteins. Our data suggest that C1ql proteins are secreted signaling molecules that bind to BAI3 and act, at least in part, to regulate synapse formation and/or maintenance.

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Section: Discussionmentioning

confidence: 97%

“…In summary, our data indicate that C1ql proteins represent a family of signaling molecules, analogous to cerebellins (39,40) and adiponectin (36,41,42), and that they act, at least in part, by binding to BAI3 as a receptor. Our study raises many additional questions, however.…”

Section: Discussionmentioning

confidence: 99%

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

Bolliger¹,

Martinelli²,

Südhof

2011

Proc. Natl. Acad. Sci. U.S.A.

162

168

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“…5 and 6). Apart from Nxph, prototypical binding partners of Nrxn are neuroligins (13,14), LRRTMs (15,16), and cerebellin/GluRδ2 (17,18). Physical binding has also been reported for GABA A R subunits (37); dystroglycan (68); and, very recently, calsyntenin-3 (67).…”

Section: Discussionmentioning

confidence: 99%

“…We have addressed this problem by studying neurexins and their interaction partners (5,6). Several aspects make neurexins candidates to couple local recognition/adhesion events to synaptic function: first, both extracellularly longer α-neurexins (α-Nrxn) and shorter β-neurexins (β-Nrxn) are able to induce functional synapses (7,8); second, at least α-Nrxn are essential for synaptic transmission at excitatory and inhibitory terminals (9,10); and third, α-and β-Nrxn are highly polymorphic, mostly presynaptic molecules (11,12) that interact with transsynaptic binding partners like neuroligins (13,14), LRRTMs (15, 16), or cerebellin/GluRδ2 (17,18).…”

mentioning

confidence: 99%

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Born

Breuer

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABA B receptor (GABA B R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA B R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA B R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA B R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA A R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA B R and postsynaptic GABA A R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA A R and GABA B R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. synaptic transmission | thalamus | autism | neuroligin | ultrastructure

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“…At PF-PC synapses, GluR␦2 plays a key role in the formation and maintenance of PF-PC synapses (Kashiwabuchi et al, 1995;Kurihara et al, 1997;Lalouette et al, 2001;Takeuchi et al, 2005;Matsuda et al, 2010;Uemura et al, 2010). Furthermore, GluR␦2 regulates endocytosis of AMPARs (Hirai et al, 2003) and mediates long-term depression (LTD) at PF-PC synapses (Kashiwabuchi et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Glutamate Receptor δ2 Is Essential for Input Pathway-Dependent Regulation of Synaptic AMPAR Contents in Cerebellar Purkinje Cells

Yamasaki¹,

Miyazaki²,

Azechi³

et al. 2011

J. Neurosci.

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The number of synaptic AMPA receptors (AMPARs) is the major determinant of synaptic strength and is differently regulated in input pathway-dependent and target cell type-dependent manners. In cerebellar Purkinje cells (PCs), the density of synaptic AMPARs is approximately five times lower at parallel fiber (PF) synapses than at climbing fiber (CF) synapses. However, molecular mechanisms underlying this biased synaptic distribution remain unclear. As a candidate molecule, we focused on glutamate receptor ␦2 (GluR␦2 or GluD2), which is known to be efficiently trafficked to and selectively expressed at PF synapses in PCs. We applied postembedding immunogold electron microscopy to GluR␦2 knock-out (KO) and control mice, and measured labeling density for GluA1-4 at three excitatory synapses in the cerebellar molecular layer. In both control and GluR␦2-KO mice, GluA1-3 were localized at PF and CF synapses in PCs, while GluA2-4 were at PF synapses in interneurons. In control mice, labeling density for each of GluA1-3 was four to six times lower at PF-PC synapses than at CF-PC synapses. In GluR␦2-KO mice, however, their labeling density displayed a three-to fivefold increase at PF synapses, but not at CF synapses, thus effectively eliminating input pathway-dependent disparity between the two PC synapses. Furthermore, we found an unexpected twofold increase in labeling density for GluA2 and GluA3, but not GluA4, at PF-interneuron synapses, where we identified low but significant expression of GluR␦2. These results suggest that GluR␦2 is involved in a common mechanism that restricts the number of synaptic AMPARs at PF synapses in PCs and molecular layer interneurons.

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Cbln1 Is a Ligand for an Orphan Glutamate Receptor δ2, a Bidirectional Synapse Organizer

Cited by 325 publications

References 25 publications

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Glutamate Receptor δ2 Is Essential for Input Pathway-Dependent Regulation of Synaptic AMPAR Contents in Cerebellar Purkinje Cells

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