Role of GPCRs and G‐αs in the antidepressant action of ketamine

Abstract

Ketamine produces rapid and robust antidepressant effects in depressed patients within hours of administration, often when traditional antidepressant compounds have failed to alleviate symptoms even after 2 months of treatment. We hypothesized that ketamine would translocate Gas from lipid rafts to non‐raft microdomains, similarly to other antidepressants but with a distinct, abbreviated treatment duration. C6 glioma and C6 cells stably transfected with G‐αs‐GFP were treated with 10uM ketamine for 15 minutes, which translocated Gas from lipid raft domains to non‐raft domains. Other NMDA antagonist did not translocate Gas from lipid raft to non‐raft domains. The ketamine induced Gas plasma membrane redistribution allows increased functional coupling of Gas and adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Furthermore, increased intracellular cAMP increased phosphorylation of cAMP response element‐binding protein (CREB), which, in turn, increased BDNF expression. These results reveal a novel antidepressant mechanism mediated by acute ketamine treatment in glial cells that may contribute to ketamine's powerful antidepressant effect.