Review
Regulation of mglu7 receptors by proteins that interact with the intracellular C-terminus

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Abstract

The metabotropic glutamate type 7 (mglu7) receptor is a widely distributed, mainly presynaptic Group III mglu receptor that can regulate glutamate release. Recently, largely as a result of the identification of specific proteins that interact with the C-terminal domain of this receptor, considerable progress has been made towards understanding some of the mechanisms that underlie the regulation, signal transduction pathways and targeting of mglu7 receptors. This has led to the proposal that there are three distinct functionally relevant domains present in the intracellular C-terminus of this receptor: (1) a proximal intracellular signalling domain that interacts with G-protein βγ-subunits and the Ca2+ sensor Ca2+–calmodulin, and is phosphorylated by protein kinase; (2) a central domain thought to provide a signal for axonal targeting; and (3) an extreme PDZ-binding motif that interacts with the protein kinase C interacting protein, PICK1.

Section snippets

Functional roles of mglu7 receptors

Over recent years, an increasing number of proteins have been identified that interact with the C-termini of mglu receptors. There is now considerable evidence to suggest that the synaptic distributions and functional properties of mglu receptors can be regulated via these interactions. An overview of the C-terminal domains of mglu receptor splice variants, and the importance of both C-terminus splice variation and putative PDZ-binding motifs in specifying proteins that interact with mglu

Interaction domains on the C-terminus of the mglu7 receptor

Several recent studies have shown that several proteins can interact with the C-terminus of mglu7 receptors. On the basis of the nature of these interacting proteins, the C-terminus can be divided into three domains (Fig. 1).

Concluding remarks

The regulation of glutamate receptors at synaptic membranes is a dynamic process that is dependent on a complex series of protein–protein interactions. Three regions of the C-terminus of mglu7 receptors have been designated as interacting with different sets of proteins (Fig. 1): (1) the proximal region that is potentially involved in intracellular signalling mechanisms; (2) the central region that is potentially involved in axonal–dendritic targeting; and (3) the distal amino acid residues

Acknowledgements

Our research was supported in part by research grants from the MRC (UK), the Wellcome Trust (UK) and the Ministry of Education, Science and Culture of Japan. We are grateful to Steve Fitzjohn, Herman van der Putten, Guido Meyer, Trevor J. Bushell, Anne Marie Craig, Helene Boudin and Yoshiaki Nakajima for their useful comments.

References (37)

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    Truncation of the extreme C terminus (mGluR7 Δ907) to remove the PDZ ligand, further truncation to disrupt the α-tubulin-binding domain (mGluR7 Δ893) (Saugstad et al., 2002), or a single-point mutation in the PDZ ligand (mGluR7 V914P), which disrupts binding to PICK1 (Dev et al., 2000; Hirbec et al., 2002; Perroy et al., 2002), all increased constitutive internalization of mGluR7, with trafficking of mGluR7 Δ907, mGluR7 Δ893, or mGluR7 V914P being indistinguishable. The PDZ ligand on mGluR7 directly interacts with PICK1 (Boudin et al., 2000; Dev et al., 2000, 2001; El Far et al., 2000; Enz and Croci, 2003; Fagni et al., 2004; Hirbec et al., 2002; Perroy et al., 2002). Furthermore, PICK1 binds to PKCα (Staudinger et al., 1997, 1995) and modulates the phosphorylation of mGluR7 (Dev et al., 2000, 2001).

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