A Postreceptor Intervention

Science Signaling  22 Jun 2010:
Vol. 3, Issue 127, pp. ec188
DOI: 10.1126/scisignal.3127ec188

Selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs), which increase synaptic concentrations of serotonin, are the most widely used class of antidepressant medications. Both the antidepressant activity of the SSRIs and their untoward side effects are thought to involve activation of 5-HT1 receptors, a class of G protein–coupled receptors (GPCRs) that signal through the Gαi/o family of heterotrimeric guanine nucleotide–binding proteins. Noting that in vitro data suggest that 5-HT1 receptors preferentially interact with Gαi2, Talbot et al. explored the effects in knock-in mice of a point mutation in Gαi2 (Gαi2G184S) that disrupts Gαi2 association with regulator of G protein signaling (RGS) proteins and would thereby be expected to prolong its activity. Compared with wild-type littermates, mice homozygous or heterozygous for Gαi2G184S showed antidepressant-like behavior (decreased immobility in tail suspension and forced-swim tests), effects that were reversed by the 5-HT1A antagonist WAY 100635. Similarly, Gαi2G184S/G184S mice showed reduced novelty-induced hypophagia (consistent with the behavior of mice chronically administered antidepressants), as well as behaviors consistent with anxiolytic activity. The heterozygous Gαi2G184S/+ mice showed increased sensitivity to the antidepressant-like effects of the 5-HT1A agonist 8-OH-DPAT and the SSRI fluvoxamine (assessed by immobility in the tail suspension test) but not to 8-OH-DPAT–induced hypothermia or to the behavioral effects of non-SSRI antidepressants. Phosphorylation of glycogen synthase kinase-3β (GSK3β) on Ser9 has been implicated in the behavioral effects of the SSRIs, and knock-in mice showed increased basal GSK3β Ser9 phosphorylation in cortex and hippocampus, an effect that was lost when they were treated with WAY 100635. The authors propose that modulation of 5-HT1A receptor–associated Gαi2 activity—either through functionally selective 5-HT1A agonists or by targeting the appropriate population of RGS proteins—could thus conceivably provide a more selective approach to antidepressant therapy.

J. N. Talbot, E. M. Jutkiewicz, S. M. Graves, C. F. Clemans, M. R. Nicol, R. M. Mortensen, X. Huang, R. R. Neubig, J. R. Traynor, RGS inhibition at Gαi2 selectively potentiates 5-HT1A–mediated antidepressant effects. Proc. Natl. Acad. Sci. U.S.A. 107, 11086–11091 (2010). [Abstract] [Full Text]