The Influence of Specific Adenylyl Cyclase Isoform Expression on Antidepressant Response

Antidepressant drug development has stagnated and new targets are needed. The literature as a whole does not seem to widely consider the notion of antidepressant action in a way that is both non-canonical and significant or fundamental to the drug's mechanism. Ostensibly, the major available drug classes act through targeting monoamine systems, but the monoamine hypothesis fails to explain many findings in depression and antidepressant effects: How, for example, do cells lacking reputake transporters respond to antidepressants, and in a way that recapitulates the fundamental biochemical deviations seen in depression? Where are these drugs acting, and what factors determine one cell's response to antidepressant drugs vs. another cell's response? A long-standing finding of the Rasenick laboratory describes an effect of antidepressant on G protein systems in vitro, in cell lines such as C6 glioma and PC12 pheochromocytoma, both neuroectodermal derivatives. These cell lines show a predictable response to a variety of commonly used antidepressant compounds and classes. However, not all cell lines, such as HEK293, show these responses. Specifically, the antidepressant-responsive cells show a redistribution of G protein Gs from lipid raft to non-raft membrane fractions with increased functional coupling of Gs and adenylyl cyclase, the reciprocal of changes observed in samples from depressed patients. This redistribution is not accompanied by a change in total membrane Gs content. However, Gi and Gq are unaffected. Biochemically, these changes are evidenced by increases in cAMP production compared to untreated controls, subsequent to stimulation with agonists of GPCR-mediated cAMP production. Yet, these cells do not express the serotonin retupake transporter (SERT) or other monoamine reuptake transporters. It appears that the effect of antidepressants on G protein signaling is non-canonical and does not involve monoamine reuptake or other action at a reuptake transporter. The purpose of this study is to further examine contributors to this antidepressant response, with particular emphasis on cellular adenylyl cyclase isoform expression, to further understanding of antidepressants’ mechanisms of action in the search for newer and better treatments.