Related GPCRs couple differently to G_s: preassociation between G protein and 5-HT₇ 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-HT₄ and 5-HT₇ 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-HT₇ receptors markedly reduced the diffusion of both Gα and Gβγ at the cell surface, which indicated 5-HT₇ receptor preassociation with G_s. This is in sharp contrast to the 5-HT₄ 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-HT₇ 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.-Andressen, K. W., Ulsund, A. H., Krobert, K. A., Lohse, M. J., Bünemann, M., Levy, F. O. Related GPCRs couple differently to G_s: preassociation between G protein and 5-HT₇ serotonin receptor reveals movement of Gα_s upon receptor activation.

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