LAUSR

&NA; 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 G&agr;q‐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’. HighlightsGlutamate indirectly gates the orphan GluD2 channels through mGlu1 receptors.mGlu1‐induced Gq‐PLC‐PKC activation is required to open GluD2 channels.This molecular gating of GluD2 channels controls the Parallel Fiber – Purkinje Cell cerebellar synapse.