mGlu1 receptor canonical signaling pathway contributes to the opening of the orphan GluD2 receptor

Neuropharmacology. 2017 Mar 15:115:92-99. doi: 10.1016/j.neuropharm.2016.06.001. Epub 2016 Jun 6.


The orphan Glutamate receptor Delta2 (GluD2) intrinsic ion channel activity is indirectly triggered by glutamate through stimulation of the metabotropic glutamate receptor 1 (mGlu1), in cerebellar Purkinje cells. However, the mechanisms of GluD2 ion channel opening are entirely unknown. In this work, we investigated the signaling pathways underlying the mGlu1-induced GluD2 current, performing whole-cell voltage-clamp recordings from mGlu1 and GluD2 transfected HEK293 cells. We show that the activation of GluD2 channels via DHPG-induced mGlu1 stimulation is Gαq-dependent. Moreover, inhibition of the downstream components of the mGlu1 canonical signaling pathway PLC and PKC with U73122 and GF109203X, respectively, strongly reduced the DHPG-induced GluD2 current. These results were further confirmed on endogenous receptors at the Parallel Fiber - Purkinje Cell cerebellar synapse, indicating that the opening of the GluD2 channel by mGlu1 receptor mobilizes the canonical Gq-PLC-PKC pathway. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Keywords: Cross-talk; GluD2; Glutamate receptors; mGlu1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cerebellum / drug effects
  • Cerebellum / physiology
  • Estrenes / pharmacology
  • HEK293 Cells
  • Humans
  • Indoles / pharmacology
  • Maleimides / pharmacology
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Organ Culture Techniques
  • Pyrrolidinones / pharmacology
  • Receptors, Glutamate / physiology*
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Estrenes
  • Indoles
  • Maleimides
  • Pyrrolidinones
  • Receptors, Glutamate
  • Receptors, Metabotropic Glutamate
  • glutamate receptor delta 2
  • metabotropic glutamate receptor type 1
  • 1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
  • Methoxyhydroxyphenylglycol
  • bisindolylmaleimide I
  • 3,4-dihydroxyphenylglycol