Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs.
Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G(i)-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.
PubMed ID: 22118459
PMC ID: PMC3255795
Article link: Cell.
Grant support: 1R01DA02694702 NIDA NIH HHS , 5R01MH084894 NIMH NIH HHS, DA026434 NIDA NIH HHS , F30HL097582 NHLBI NIH HHS , HL59949 NHLBI NIH HHS , MH084894 NIMH NIH HHS, MH091360 NIMH NIH HHS, R01 HL059949-15 NHLBI NIH HHS , R01 MH084894-04 NIMH NIH HHS, SRC1DA02811202 NIDA NIH HHS , K02 DA026434-04 NIDA NIH HHS , R21 MH091360-02 NIMH NIH HHS, R01 MH084894 NIMH NIH HHS, R01 HL059949 NHLBI NIH HHS , K02 DA026434 NIDA NIH HHS , R21 MH091360 NIMH NIH HHS
Genes referenced: gprc6a