Homer-Dependent Cell Surface Expression of Metabotropic Glutamate Receptor Type 5 in Neurons

doi:10.1006/mcne.2002.1100

Molecular and Cellular Neuroscience

Volume 20, Issue 2, June 2002, Pages 323-329

https://doi.org/10.1006/mcne.2002.1100 Get rights and content

Abstract

The metabotropic glutamate (mGlu) receptors are a family of receptors involved in the tuning of fast excitatory synaptic transmission in the brain. Experiments performed in heterologous expression systems suggest that cell surface expression of group I mGlu receptors is controlled by their auxiliary protein, Homer. However, whether or not this also applies to neurons remains controversial. Here we show that in cultured cerebellar granule cells, the group I mGlu receptor subtype, mGlu5, transfected alone is functionally expressed at the surface of these neurons. Transfected Homer1b caused intracellular retention and clustering of this receptor at synaptic sites. Recombinant Homer1a alone did not affect cell surface expression of the receptor, but in neurons transfected with Homer1b, excitation-induced expression of native Homer1a reversed the intracellular retention of mGlu5 receptors, resulting in the receptor trafficking to synaptic membranes. Transfected Homer1a also increased the latency and amplitude of the mGlu5 receptor Ca²⁺ response. These results indicate that Homer1 proteins regulate synaptic cycling and Ca²⁺ signaling of mGlu5 receptors, in response to neuronal activity.

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Citation Excerpt :
Unlike long form Homers, Homer-1a has a relatively small effect on cell surface expression and clustering of Group I mGlu receptors (Ango et al., 2000; Ango et al., 2001; Ango et al., 2002; Ciruela et al., 1999; Roche et al., 1999). Homer-1a expression induced by neuronal activation reverses the intracellular retention of mGlu5 mediated by Homer-1b and promotes cell surface targeting of mGlu5 (Ango et al., 2002). Induction of Homer-1a expression by conditioning depolarization reduces the internalization and increases surface expression of mGlu1 in a MAPK-dependent manner in HEK293 cells and cerebellar Purkinje neurons (Minami et al., 2003) (Fig. 2).
The metabotropic glutamate receptors (mGlu receptors) are G protein-coupled receptors that bind to the excitatory neurotransmitter glutamate and are important in the modulation of neuronal excitability, synaptic transmission, and plasticity in the central nervous system. Trafficking of mGlu receptors in and out of the synaptic plasma membrane is a fundamental mechanism modulating excitatory synaptic function through regulation of receptor abundance, desensitization, and signaling profiles. In this review, we cover the regulatory mechanisms determining surface expression and endocytosis of mGlu receptors, with particular focus on post-translational modifications and receptor-protein interactions. The literature we review broadens our insight into the precise events defining the expression of functional mGlu receptors at synapses, and will likely contribute to the successful development of novel therapeutic targets for a variety of developmental, neurological, and psychiatric disorders.
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Regular ArticleHomer-Dependent Cell Surface Expression of Metabotropic Glutamate Receptor Type 5 in Neurons

Abstract

Neuropharmacology

Trends Neurosci.

Neuron

Neuron

Neuron

J. Biol. Chem.

Neuron

Neuron

Neuron

Neuron

Neuron

Curr. Opin. Neurobiol.

Dendritic and axonal targeting of type 5 metabotropic glutamate receptor is regulated by Homer1 proteins and neuronal excitation

J. Neurosci.

Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer

Nature

Inositol phosphate and cell signalling

Nature

Homer: A protein that selectively binds metabotropic glutamate receptors

Nature

The C-terminal domains of the GABA(b) receptor subunits mediate intracellular trafficking but are not required for receptor signaling

J. Neurosci.

Modulation of big K+ channel activity by ryanodine receptors and L-type Ca2+ channels in neurons

Eur. J. Neurosci.

Regular Article
Homer-Dependent Cell Surface Expression of Metabotropic Glutamate Receptor Type 5 in Neurons