Related GPCRs couple differently to G(s): preassociation between G protein and 5-HT(7) serotonin receptor reveals movement of Gα(s) upon receptor activation

How GPCRs and G proteins interact is important for their biologic functions and their functions as pharmacologic targets. It is still an open question whether receptors and G proteins are preassembled in a complex or interact only after receptor activation. We compared the propensity of the two G(s)-coupled serotonin (5-HT) receptors 5-HT(4) and 5-HT(7) to associate with G protein prior to agonist activation. Combining receptor-immobilized fluorescence recovery after photobleaching and fluorescence resonance energy transfer methodologies, we observed that 5-HT(7) receptors markedly reduced the diffusion of both Gα and Gβγ at the cell surface, which indicated 5-HT(7) receptor preassociation with G(s). This is in sharp contrast to the 5-HT(4) receptor for which the diffusion of Gαβγ was not modified, and agonist activation brought together the receptor and Gγ, which is consistent with interaction by collision coupling. Agonist activation of 5-HT(7) dissociated Gγ from the receptor, whereas Gα(s) underwent a rapid conformational change with respect to both Gγ and the receptor, followed by a slower dissociation of Gγ from both Gα(s) and the receptor. Taken together, these data demonstrate a different propensity among receptors to preassociate with G protein in the absence of ligand and reveals a rapid conformational change in Gα(s) upon activation by the receptor

Novel Benzo[b]thiophene Derivatives as New Potential Antidepressants with Rapid Onset of Action

We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT7R and 5-HTT were selected to probe using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action

Novel Benzo[b]thiophene Derivatives as New Potential Antidepressants with Rapid Onset of Action

We report benzo[b]thiophene derivatives synthesized according to a dual strategy. 8j, 9c, and 9e with affinity values toward 5-HT7R and 5-HTT were selected to probe using the forced swimming text (FST). The results showed significant antidepressant activity after chronic treatment. 9c was effective in reducing the immobility time in FST even after acute treatment. These findings identify these compounds as a new class of antidepressants with a rapid onset of action