Figure 1

G protein-dependent signaling and behavioral responses that require a GPCR heterocomplex. Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, all have in common a high affinity for the serotonin 5-HT_2A receptor. Metabotropic glutamate 2 receptor (mGlu₂) and serotonin 5-HT_2A receptor form a specific functional GPCR heterocomplex in mammalian brain and in tissue culture preparations. mGlu₂ transmembrane domains 4/5 mediate association with the 5-HT_2A receptor. When 5-HT_2A and mGlu₂ are prevented from forming a receptor heterocomplex, activation of 5-HT_2A by LSD elicits signaling characteristic of G_q/11-protein subtypes. In contrast, LSD acting at the 5-HT_2A-mGlu₂ receptor heterocomplex activates both G_q/11- and G_i/o-dependent signaling. Head-twitch behavior is reliably and robustly elicited by hallucinogenic 5-HT_2A agonists, and is absent in mGlu₂ knockout mice.