An orphan ionotropic glutamate receptor: The δ2 subunit

doi:10.1016/j.neuroscience.2008.02.050

Neuroscience

Volume 158, Issue 1, 12 January 2009, Pages 67-77

https://doi.org/10.1016/j.neuroscience.2008.02.050 Get rights and content

Abstract

The glutamate receptor δ2 (GluRδ2) subunit has been classified as an ionotropic glutamate receptor on the basis of the amino acid sequence. It is considered an orphan receptor since no physiological ligand has so far been identified. GluRδ2 is selectively localized at the parallel fiber–Purkinje cell (PF–PC) synapses in the adult cerebellar cortex, where it promotes and maintains the integrity of these synapses. Mutations of the gene coding for the GluRδ2 are also accompanied by reduced regression of the climbing fiber (CF) multiple innervation, loss of long term depression (LDT) and by specific cerebellar dysfunctions involving motor coordination, motor learning and impairment of fear memory consolidation. In addition, it participates in the competition between heterologous afferent fibers to PCs. On the whole, it appears that during evolution GluRδ2 has lost its channel properties to acquire the function of an activity-dependent adhesion molecule with the key role of orchestrating the architecture of the PC innervation to allow two different patterns of signal elaboration; the CF all-or-none depolarization in the proximal dendritic domain and a highly discriminative capacity in the distal domain.

Section snippets

The gene coding the GluRδ2: Expression and protein localization

In mice the Glutamate receptor ionotropic delta-2 (Grid2) gene is located on chromosome 6 (29.6 cM) and consists of 16 exons covering a region of approximately 1.4 Mb. Many spontaneous mutations occur in this gene (Wang et al., 2003). In fact, at least 18 ataxic mutant mice (Mouse Genome Informatics, 2007) are linked to the Grid2 locus (Lalouette et al., 2001). Recently, fragile sites have been identified in the mouse Grid2 gene and its human ortholog (Rozier et al 2004, Robinson et al 2005).

The GluRδ2 protein structure and function

The GluRδ2 subunit has an architecture similar to other ionotropic glutamate receptor (iGluR) subunits and consists of an extracellular amino-terminus (N-terminus) which harbors a bacterial periplasmic amino acid (aa) leucine/isoleucine/valine-binding protein (LIVBP) –like domain and a bipartite lysine/arginine/ornithine-binding protein (LAOBP)-like domain, three transmembrane domains (TM1, TM3 and TM4), an ion-channel-forming re-entrant loop segment (TM2) and a cytoplasmic carboxyl-terminal

The function of GluRδ2 provided by studies on animal models

Studies conducted on spontaneous mutant mice, such as the GluRδ2^Lc and the ho, on GluRδ2 KO mice and on transgenic mice have provided some clues to the function of the GluRδ2 subunit. All these arguments have been extensively reviewed (Yuzaki 2003b, Yuzaki 2005, Vogel et al 2007). This article focuses on the roles of the GluRδ2 in the stabilization of PF–PC synapses and in the heterologous axonal competition.

GluRδ2 and LTD induction

LTD occurring at PF–PC synapses is a form of synaptic plasticity which is considered a cellular basis for motor learning (Ito, 2001). It is induced by conjunctive activation of PFs and CFs and requires activation of mGluR1 (Conquet et al., 1994), voltage-gated Ca²⁺ channels (Levenes et al., 1998) and AMPA type GluRs (Linden and Connor, 1993) through their endocytotic internalization (Matsuda et al 1999, Chung et al 2000, Xia et al 2000). GluRδ2 also is crucial for LTD induction in PCs. In

GluRδ2 and behavior

Additional sources of information on the GluRδ2 subunit come from studies related to behavioral observations in mutant or KO mice. The striking deficiency of the number and the altered morphology of the PF–PC synapses provides a plausible explanation for the ataxic gait and other motor disabilities (Kashiwabuchi et al., 1995) as well as more complex behavioral deficiencies (Sacchetti et al., 2005).

Eye-blink conditioning depends on the cerebellum (McCormick et al 1982, Chen et al 1996, Thompson

Discussion and conclusions

iGluRs are considered multifunctional proteins that are used in a wide range of neurons not only as components of ion channels that contribute to their electrical properties, but also as cell surface molecules that mediate signal transduction events within specific neuronal microdomains. GluRδ2 has peculiar characteristics which make it definitely different from iGluRs.

A first peculiar feature of the GluRδ2 is that, despite the fact that its structural profile is similar to iGluRs, it does not

Acknowledgments

We thank Dr. Michisuke Yuzaki for helpful discussion and for critically reading the manuscript. This work was supported by grants from Italian MIUR, Ministry of Health, European Community contract number 512039, Regione Piemonte, ASI and Compagnia San Paolo.

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¹: G.M. and R.C. contributed equally to this work.

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Interacting PartnerReviewAn orphan ionotropic glutamate receptor: The δ2 subunit

Abstract

Section snippets

The gene coding the GluRδ2: Expression and protein localization

The GluRδ2 protein structure and function

The function of GluRδ2 provided by studies on animal models

GluRδ2 and LTD induction

GluRδ2 and behavior

Discussion and conclusions

Acknowledgments

Biochem Biophys Res Commun

Prog Neurobiol

Psychoneuroendocrinology

Trends Cell Biol

Neurosci Res

Neurosci Lett

J Biol Chem

Genomics

Neuron

Cell

Brain Res Mol Brain Res

Brain Res Mol Brain Res

Brain Res

Neuroscience

Neuron

Prog Neurobiol

Curr Opin Neurobiol

FEBS Lett

J Biol Chem

J Biol Chem

Brain Res

Neuroscience

Neuron

Neuron

Neuron

Brain Dev

Brain Dev

Brain Res

Trends Neurosci

Brain Res Dev Brain Res

Int Rev Neurobiol

Mol Cell Neurosci

Brain Res

Eur J Neurosci

Neuron

Brain Res Mol Brain Res

Biochem Biophys Res Commun

Mol Cell Neurosci

Biochem Biophys Res Commun

Neuron

Neurosci Res

Structure of a glutamate-receptor ligand-binding core in complex with kainate

Nature

Functional synaptogenesis in the cerebellar cortex after inferior olive lesion

Glutamate receptor delta2 subunit in activity-dependent heterologous synaptic competition

J Neurosci

Impaired classical eye-blink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice

J Neurosci

Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins

J Neurosci

Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1

Nature

Subcortical and cortical brain activity during the feeling of self-generated emotions

Nat Neurosci

The glutamate receptor ion channels

Pharmacol Rev

Structural determinants of barium permeation and rectification in non-NMDA glutamate receptor channels

J Neurosci

Interacting Partner
Review
An orphan ionotropic glutamate receptor: The δ2 subunit