Presynaptic Clustering of mGluR7a Requires the PICK1 PDZ Domain Binding Site

Abstract

Aggregation of neurotransmitter receptors at pre- and postsynaptic structures is crucial for efficient neuronal communication. In contrast to the wealth of information about postsynaptic specializations, little is known about the molecular organization of presynaptic membrane proteins. We show here that the metabotropic glutamate receptor mGluR7a, which localizes specifically to presynaptic active zones, interacts in vitro and in vivo with PICK1. Coexpression in heterologous systems induces coclustering dependent upon the extreme C terminus of mGluR7a and the PDZ domain of PICK1. mGluR7a and PICK1 localize to excitatory synapses in hippocampal neurons. Furthermore, whereas transfected mGluR7a clusters at presynaptic sites, mGluR7adelta3 lacking the PICK1 binding site targets to axons but does not cluster. These results suggest that PICK1 is a component of the presynaptic machinery involved in mGluR7a aggregation and in modulation of glutamate neurotransmission.

The PDZ-binding domain is essential for the dendritic targeting of 5-HT2A serotonin receptors in cortical pyramidal neurons in vitro

“…the presynaptic terminal in axon). The signal that mediates selective sorting to axons was presumed to be upstream of the PDZ-binding domain in the central portion of the carboxyl-terminus of the mGluR7 receptor (Stowell and Craig, 1999;Boudin et al, 2000). In contrast, our studies directly implicate the PDZ-binding domain in targeting 5-HT 2A receptors to the dendritic compartment.…”

“…There is one other account that ascribes to the PDZ-binding domain any role for the selective targeting of GPCRs. Specifically, the PDZ-binding domain of the mGluR7 receptor is recognized by PICK1, a PKC␣-binding protein, and association with PICK1 serves to cluster mGluR7 to the presynaptic active zone in cultured hippocampal neurons (Boudin et al, 2000;Boudin and Craig, 2001). The PDZ-binding domain in the case of mGluR7 thus serves to target mGluR7 receptors to a specialized region within a subcellular compartment (i.e.…”

“…For some GPCRs, particularly metabotropic glutamate receptors, several studies have identified the distal end of the carboxyl terminus as the sorting motif (Stowell and Craig, 1999;Boudin et al, 2000;Jolimay et al, 2000). Interestingly, the last four amino acids (VSCV) of the carboxyl terminus of the 5-HT 2A receptor constitute a canonical Type I PDZ-binding motif (X-S/T-X-), a protein-pro-tein interaction motif that could potentially serve as a targeting signal (Kornau et al, 1995;Chung et al, 2002).…”

GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

“…In particular there has been a lot of interest in PICK1 since it was originally identified as an interactor for PKCa (Staudinger et al 1995(Staudinger et al , 1997. In addition, to PKCa and GluR2, PICK1 also interacts with a number of other proteins including mGluR7 (Boudin et al 2000;Dev et al 2000;El Far et al 2000), non-voltage-gated Na 1 channels (Baron et al 2002;Duggan et al 2002;Hruska-Hageman et al 2002) and ephrin receptors (Torres et al 1998). Although PICK1 contains only a single PDZ domain, it can also dimerize via a coiled-coil domain (Perez et al 2001) providing the possibility that PICK1 dimers could target other proteins such as PKCa to AMPARs.…”

The C Terminus of the Metabotropic Glutamate Receptor Subtypes 2 and 7 Specifies the Receptor Signaling Pathways

“…A second candidate is the PDZ domaincontaining protein, protein interacting with C kinase 1 (PICK1). This protein interacts with the very last 3 C-terminal amino acids of the mGlu7a receptor (41)(42)(43). The PDZ domain of PICK1 also interacts with PKC␣ (44) thus creating a functional complex comprising the mGlu7 receptor, a PICK1 dimer and PKC␣ (42).…”