Antidepressant treatment increases cAMP signaling by translocating Gas from lipid rafts and increasing association with type 6 adenylyl cyclase (AC6) independent of action at monoamine transporters.

Abstract

Antidepressants of different chemical classes promote sustained increases in cAMP, due, at least in part to the redistribution of Gαs from lipid rafts into non‐raft membrane fractions resulting in increased Gαs functional coupling with adenylyl cyclase (AC). This has been demonstrated in both rats and cultured neural and glial cells by a number of techniques, including cell fractionation, functional assays, and imaging studies such as Fluorescence Recovery After Photobleaching (FRAP). Unlike animal models, C6 glioma lack monoamine reuptake transporters, suggesting that mechanisms of antidepressant response entail more than inhibition of neurotransmitter reuptake inhibition. This is noteworthy, since inhibition of 5HT or NE uptake is quite rapid even though clinical effects of antidepressants require several weeks (and several days in the cellular models). Furthermore, while these neural and glial cells showed an “antidepressant response”, Gαs localization and cAMP production in kidney epithelial cells like COS7 and HEK293 were unchanged by antidepressant treatment. Similarly, membranes from liver and kidney of rats treated chronically with antidepressant did not show the same response as brain from those same animals. In this study we sought to determine whether cellular antidepressant response, with respect to increased cAMP signaling and Gαs localization, is dependent on the type of AC isoform expression. Cell lines “insensitive” to antidepressant treatment, such as HEK293, become responsive after transfection with AC6, showing translocation of Gαs from lipid rafts, both by cell fractionation and by FRAP. Likewise, knockdown of AC6 but not other adenylyl cyclase isoforms abolishes the antidepressant response in responsive cell lines such as C6 glioma. Thus, it is suggested that AC6 performs a anchoring function for Gαs outside of rafts, affixing the translocated Gαs into the non‐raft domain and facilitating an antidepressant‐induced increase in adenylyl cyclase activity.