Scaffolding group II metabotropic glutamate receptors

Abstract

This study identified 5 candidate interacting proteins for the group II mGluRs; microtubule-associated serine threonine kinase (MAST), syntrophin associated serine/threonine kinase (SAST), rhophilin-1, protein kinase C interacting cousin of thioredoxin (PICOT) and calmodulin. MAST, SAST and rhophilin-1 all contain a PDZ (Post Synaptic Density-95, Discs large, ZO-1) domain, a common protein:protein interaction domain found in many receptor scaffolding proteins. Mutation analysis of the C-tail of mGluR2 and mGluR3 suggests that they interact with MAST, SAST and rhophilin-1 through the PDZ domain although the interaction is atypical, requiring more of the receptor C-tail than initially thought to constitute the interaction domain. The interactions of MAST, SAST and rhophilin-1 with mGluR2 and mGluR3 were recapitulated biochemically utilising glutathione S-transferase pulldown experiments. The interaction of calmodulin with group II mGluRs as shown by the yeast two-hybrid screen could not be reproduced biochemically in agreement with published data, highlighting the importance of biochemically confirming candidate interactions identified in yeast two-hybrid screens. When co-expressed heterologously SAST or rhophilin-1 co-localised with group II mGluRs suggesting the interactions occur in a cellular context.  SAST is expressed in areas of the brain in which group II mGluRs are present, MAST and rhophilin-1 are present in brain but little known about the distribution, so there is potential for the interactions to have in vivo functions. These studies provide a platform for further investigation of the role of MAST, SAST and rhophilin-1 in the regulation of mGluR function.

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