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The Journal of Neuroscience, March 19, 2008, 28(12):3042-3050; doi:10.1523/JNEUROSCI.5713-07.2008

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Neurobiology of Disease
Postmortem Brain Tissue of Depressed Suicides Reveals Increased Gs Localization in Lipid Raft Domains Where It Is Less Likely to Activate Adenylyl Cyclase

Robert J. Donati,^1,3 Yogesh Dwivedi,² Rosalinda C. Roberts,⁴ Robert R. Conley,⁴ Ghanshyam N. Pandey,² and Mark M. Rasenick^1,2

Departments of ¹Physiology and Biophysics and ²The Psychiatric Institute, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612-7342, ³Basic and Health Science Department, Illinois College of Optometry, Chicago, Illinois 60616, and ⁴Maryland Psychiatric Research Center, Baltimore, Maryland 21228

Correspondence should be addressed to Dr. Mark M. Rasenick, Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, 835 South Wolcott Avenue, M/C 901, Room E202, Chicago, IL 60612-7342. Email: raz{at}uic.edu

Recent in vivo and in vitro studies have demonstrated that Gs 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 may be 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 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 is 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 to a membrane domain (lipid rafts) where it is less likely to couple to adenylyl cyclase and that antidepressants may upregulate Gs signaling via disruption of membrane microenvironments. Raft localization of Gs in human peripheral tissue may thus serve as a biomarker for depression and as a harbinger of antidepressant responsiveness.

Key words: antidepressant; depression; lipid microdomains; cerebellum; prefrontal cortex; signal transduction

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Received April 20, 2007; revised Jan. 28, 2008; accepted Jan. 30, 2008.

Correspondence should be addressed to Dr. Mark M. Rasenick, Department of Physiology and Biophysics, University of Illinois at Chicago, College of Medicine, 835 South Wolcott Avenue, M/C 901, Room E202, Chicago, IL 60612-7342. Email: raz{at}uic.edu

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