Interaction of the C‐terminal tail region of the metabotropic glutamate receptor 7 with the protein kinase C substrate PICK1

Abstract

Group III metabotropic glutamate receptors (mGluRs) are highly enriched in the presynaptic terminals of glutamatergic synapses where they mediate feedback inhibition of neurotransmitter release. Here, we used the yeast two-hybrid system to identify a direct interaction of the C-terminal tail region of mGluR7 with the rat homologue of the protein kinase C substrate PICK1. This interaction is speci®cally mediated by the very C-terminal amino acids of the receptor and can be reconstituted in human embryonic kidney 293 cells by transfection of full-length mGluR7 and PICK1 cDNAs. Quantitative b-galactosidase assays revealed that among the different group III mGluRs, mGluR7 is the major PICK1 binding partner although other subfamily members can also interact with PICK1. These data indicate that PDZ domain-containing proteins might contribute to the presynaptic localization of group III mGluRs. Materials and methods Yeast two-hybrid analysisFragments encoding the complete C-terminal tail regions of mGluR7A, 7B, 4A, 4B, 8A and 8B were generated by PCR as described (O'Connor et al., 1999), inserted into the inducible pGilda

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“…The domain structure of PICK1 is rather unique and consists of a short stretch of acidic amino acid residues at the N-terminus, which is followed by a PDZ domain that mediates interactions with the majority of the interacting partners (cf. Xu & Xia, 2007;El Far et al, 2000). The PDZ domain is connected via an approximate 40-residue linker region to a larger BAR domain (Bin/ amphiphysin/Rvs) that spans approximately half of the protein, and the C-terminus is characterized also by a stretch of acidic residues.…”

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“…PICK1 has been shown to interact with the C-terminal tail region of mGluR7 via the PDZ domain [57,94]. An uncoupling of PICK1 from the mGluR7a with an interface interfering peptide produces absence-like seizures, a special form of epilepsy [95].…”

PDZ Domain Protein-Protein Interactions: A Case Study with PICK1

“…The central α-helical coiled-coil motif of PICK1, suggested initially to span residues 139-166 [11,16], proposes now to be larger in nature covering residues 152-362 with a similar structure to the arfaptin homology domain (AHD) and Bin/amphiphysin/Rvs (BAR) domain [17][18][19][20]. Although the AHD/BAR domain in arfaptin proteins binds ARFs, the PICK1 AHD does not bind ARFs.…”

“…The ct-mGluR7 contains three distinct protein interaction and functional domains, namely, a proximal domain involved in intracellular signalling events such as G-protein βγ-subunit coupling, Ca 2+ -calmodulin interaction and PKC phosphorylation [112][113][114][115][116][117][118]; a central domain involved in axonal targeting [119]; and an extreme PDZ-binding motif that interacts with PICK1, GRIP and syntenin [13,16,21,24,77,[117][118][119]. PICK1 also interacts with mGluR3, 8a, 8b, 4a and 7b, GRIP interacts with mGluR3, 4a, 6 and 7a whereas syntenin interacts with mGluR4a, 6, 7a and 7b [16,77,120]. Furthermore, ctmGluR7b (but not ct-mGluR7a) binds the catalytic γ-subunit of protein phosphatase 1C (PP1γ1 and PP1γ2 but not PP1α1 and PP1β) where binding of PP1C does not compete with PICK1 or syntenin [121,122].…”