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Abstract
The eight pre- or/and post-synaptic metabotropic glutamatergic receptors (mGluRs) modulate rapid excitatory transmission sustained by ionotropic receptors. They are classified in three families according to their percentage of sequence identity and their pharmacological properties. mGluR4 belongs to group III and is mainly localized presynaptically. Activation of group III mGluRs leads to depression of excitatory transmission, a process that is exclusively provided by mGluR4 at parallel fiber-Purkinje cell synapse in rodent cerebellum. This function relies at least partly on an inhibition of presynaptic calcium influx, which controls glutamate release. To improve the understanding of molecular mechanisms of the mGluR4 depressant effect, we decided to identify the proteins interacting with this receptor. Immunoprecipitations using anti-mGluR4 antibodies were performed with cerebellar extracts. 183 putative partners that co-immunoprecipitated with anti-mGluR4 antibodies were identified and classified according to their cellular functions. It appears that native mGluR4 interacts with several exocytosis proteins such as Munc18-1, synapsins, and syntaxin. In addition, native mGluR4 was retained on a Sepharose column covalently grafted with recombinant Munc18-1, and immunohistochemistry experiments showed that Munc18-1 and mGluR4 colocalized at plasma membrane in HEK293 cells, observations in favor of an interaction between the two proteins. Finally, affinity chromatography experiments using peptides corresponding to the cytoplasmic domains of mGluR4 confirmed the interaction observed between mGluR4 and a selection of exocytosis proteins, including Munc18-1. These results could give indications to explain how mGluR4 can modulate glutamate release at parallel fiber-Purkinje cell synapses in the cerebellum in addition to the inhibition of presynaptic calcium influx.
Highlights
MGluR4 negatively modulates neurotransmission at glutamatergic synapses
Using proteomic approaches, we show that native mGluR4 interacts with exocytosis proteins
In this study we demonstrated that mGluR4 was able to interact with numerous exocytosis proteins including Munc18-1 and sensitive factor attachment protein receptor (SNARE) proteins such as syntaxin and synaptosomal-associated protein 25 (SNAP-25)
Summary
Munc was recently identified as a binding partner for mGluR4 by co-immunoprecipitation and GST pulldown experiments [13]. This protein has been suggested to assist in the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex syntaxin/synaptosomal-associated protein 25 (SNAP-25)/synaptobrevin during neurotransmitter vesicles exocytosis [14] via a Ca2ϩ/ calmodulin-dependent pathway. Interaction domains of mGluR4 with several exocytosis proteins were further studied by affinity chromatography experiments using peptides corresponding to the intracellular parts of mGluR4 These interactions could be involved in the molecular mechanisms underlying the depressant presynaptic action of this activated receptor in the cerebellar cortex through the control of glutamate release
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