NMDAR-independent, cAMP-dependent antidepressant actions 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. We hypothesized that ketamine would translocate Gα_s from lipid rafts to non-raft microdomains, similarly to other antidepressants but with a distinct, abbreviated treatment duration. C6 glioma cells were treated with 10 µM ketamine for 15 min, which translocated Gα_s from lipid raft domains to non-raft domains. Other NMDA antagonist did not translocate Gα_s from lipid raft to non-raft domains. The ketamine-induced Gα_s plasma membrane redistribution allows increased functional coupling of Gα_s and adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Moreover, increased intracellular cAMP increased phosphorylation of cAMP response element-binding protein (CREB), which, in turn, increased BDNF expression. The ketamine-induced increase in intracellular cAMP persisted after knocking out the NMDA receptor indicating an NMDA receptor-independent effect. Furthermore, 10 µM of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) also induced Gα_s redistribution and increased cAMP. These results reveal a novel antidepressant mechanism mediated by acute ketamine treatment that may contribute to ketamine's powerful antidepressant effect. They also suggest that the translocation of Gα_s from lipid rafts is a reliable hallmark of antidepressant action that might be exploited for diagnosis or drug development.

SUBMITTER: Wray NH 

PROVIDER: S-EPMC8011999 | biostudies-literature |

REPOSITORIES: biostudies-literature