Lateral diffusion of G s in the plasma membrane is decreased after chronic but not acute antidepressant treatment: Role of lipid raft and non-raft membrane microdomains

GPCR signaling is modified both in major depressive disorder and by chronic antidepressant treatment. Endogenous G s redistributes from raft-to nonraft-membrane fractions after chronic antidepressant treatment. Modification of G protein anchoring may participate in this process. Regulation of Gs signaling by antidepressants was studied using fluorescence recovery after photobleaching (FRAP) of GFP-Gs. Here we find that extended antidepressant treatment both increases the half-time of maximum recovery of GFP-Gs and decreases the extent of recovery. Furthermore, this effect parallels the movement of Gs out of lipid rafts as determined by cold detergent membrane extraction with respect to both dose and duration of drug treatment. This effect was observed for several classes of compounds with antidepressant activity, whereas closely related molecules lacking antidepressant activity (eg, R-citalopram) did not produce the effect. These results are consistent with previously observed antidepressant-induced translocation of Gs, but also suggest an alternate membrane attachment site for this G protein. Furthermore, FRAP analysis provides the possibility of a relatively high-throughput screening tool for compounds with putative antidepressant activity.