Synergy between Gq and Gi proteins for the antipsychotic-like effects of mGlu2 receptors.

In hippocampal neurons, Gi/o-coupled mGlu2 receptors generate calcium signals via crosstalk with a coexpressed Gq-coupled receptor, requiring PAFR activity.

• Why it matters: GPCRs can reshape each other’s signaling, but how this operates in brain circuits and affects therapeutic outcomes is unclear.
• What they did: The study tested mGlu2-driven calcium signaling in neurons and identified an essential role for constitutively active PAFR, with effects largely blocked by PAFR inverse agonists and genetic variants.
• The result: The mGlu2–PAFR interaction is required for the cognitive and behavioral rescue from mGlu2 agonists in a mouse model of NMDA receptor hypofunction, informing psychiatric drug strategies.

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