Preso1 dynamically regulates group I metabotropic glutamate receptors

Abstract

Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein–coupled receptors (GPCRs) that are expressed at excitatory synapses in brain and spinal cord. GPCRs are often negatively regulated by specific G protein–coupled receptor kinases and subsequent binding of arrestin-like molecules. Here we demonstrate an alternative mechanism in which group I mGluRs are negatively regulated by proline-directed kinases that phosphorylate the binding site for the adaptor protein Homer, and thereby enhance mGluR–Homer binding to reduce signaling. This mechanism is dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site. Genetic ablation of Preso1 prevents dynamic phosphorylation of mGluR5, and Preso1−/− mice exhibit sustained, mGluR5-dependent inflammatory pain that is linked to enhanced mGluR signaling. Preso1 creates a microdomain for proline-directed kinases with broad substrate specificity to phosphorylate mGluR and to mediate negative regulation.

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

“…This is in accordance with sequestration of mGlu1/5 by Homer1a, which is translated locally in an activity-driven manner after DHPG treatment, thereby reducing the interaction of the long forms of Homer with mGlu1/5 (Kammermeier et al, 2000;Kammermeier and Worley, 2007). However, it should be noted that others have reported an increase in mGlu5-Homer interaction after DHPG treatment (Rong et al, 2003;Hu et al, 2012). These differences may be attributable to the use of a different model system and duration of mGlu5 agonist exposure.…”

Alterations of mGluR5 and its endogenous regulators Norbin, Tamalin and Preso1 in schizophrenia: towards a model of mGluR5 dysregulation

“…NMDAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and mGluRs), including Homer1, are reportedly altered in some schizophrenia studies [see 35]. However, additional proteins that critically modulate mGluR5 activity have also been identified [12,14,37], but have not yet been directly examined in the brains of people with schizophrenia.…”

“…Furthermore, the scaffold protein Preso1 (FRMPD4) was also reported to be essential to mGluR5 signaling, with Preso1-dependent phosphorylation of mGluR5 serving to down-regulate mGluR5 signaling under control conditions in cellular assays, whilst Preso1 −/− mice exhibit characteristics reminiscent of enhanced mGluR5 signaling [12]. Preso1 additionally modulates mGluR5 coupling to the scaffold protein Homer [12], which has been previously associated with schizophrenia [6,31].…”

“…Preso1 additionally modulates mGluR5 coupling to the scaffold protein Homer [12], which has been previously associated with schizophrenia [6,31]. However, the role of Preso1 in schizophrenia-relevant paradigms has not been assessed.…”

Structural basis for the recognition of the scaffold protein Frmpd4/Preso1 by the TPR domain of the adaptor protein LGN

“…1a) and interacts with LGN via a region in the C-terminal half which shows considerable similarity to part of the LGN- (Yuzawa et al, 2011). Frmpd4 has been reported to modulate dendritic spine morphogenesis (Lee et al, 2008) and to stabilize the interaction between the group I metabotropic glutamate receptors mGluR1/5 and the adaptor protein Homer, thereby attenuating calcium influx into spinal neurons (Hu et al, 2012), although the role of the LGNFrmpd4 interaction in these events remains to be elucidated.…”