Postmortem brain tissue of depressed suicides reveals increased Gsα localization in lipid raft domains where it is less likely to activate adenylyl cyclase

Recent in vivo and in vitro studies have demonstrated that Gs alpha migrates from a Triton X-100 (TX-100)-insoluble membrane domain (lipid raft) to a TX-100-soluble nonraft membrane domain in response to chronic, but not acute, treatment with tricyclic or selective serotonin reuptake inhibitor antidepressants. This migration resulted in a more facile association with adenylyl cyclase. Our hypothesis is that Gs alpha maybe ensconced, to a greater extent, in lipid rafts during depression, and that one action of chronic antidepressant treatment is to reverse this. In this postmortem study, we examined Gs alpha membrane localization in the cerebellum and prefrontal cortex of brains from nonpsychiatric control subjects and suicide cases with confirmed unipolar depression. Sequential TX-100 and TX-114 detergent extractions were performed on the brain tissue. In the cerebellum, the ratio of TX-100/TX-114-soluble Gs alpha is similar to 2:1 for control versus depressed suicides. Results with prefrontal cortex samples from each group demonstrate a similar trend. These data suggest that depression localizes Gs alpha to a membrane domain (lipid rafts) where it is less likely to couple to adenylyl cyclase and that antidepressants may upregulate Gs alpha signaling via disruption of membrane microenvironments. Raft localization of Gs alpha in human peripheral tissue may thus serve as a biomarker for depression and as a harbinger of antidepressant responsiveness.