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

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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’.

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