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Mechanisms of Agonism and Inverse Agonism at Serotonin 5‐HT1A Receptors

Abstract: Mechanisms of agonist and inverse agonist action at the serotonin 5‐HT1A receptor have been studied using the modulation of guanosine 5′‐O‐(3‐[35S]thiotriphosphate) ([35S]GTPγS) binding in membranes of Chinese hamster ovary (CHO) cells expressing the receptor (CHO‐5‐HT1A cells). A range of agonists increased [35S]GTPγS binding with different potencies and to different maximal extents, whereas two compounds, methiothepin and spiperone, inhibited both agonist‐stimulated and basal [35S]GTPγS binding, thus exhibiting inverse agonism. Potencies of agonists to stimulate [35S]GTPγS binding in membranes from CHO‐5‐HT1A cells were reduced by adding increasing concentrations of GDP to assays, whereas changes in sodium ion concentration did not affect agonist potency. The maximal effect of the agonists was increased by increasing sodium ion concentrations. The affinities of agonists in ligand binding assays were unaffected by changes in sodium ion concentration. Increasing GDP in the assays of the inverse agonists increased potency for spiperone to inhibit [35S]GTPγS binding and had no effect for methiothepin, in agreement with the sensitivity of these compounds to guanine nucleotides in ligand binding assays. Potencies for these inverse agonists were unaffected by changes in sodium ion concentration. These data were simulated using the extended ternary complex model. These simulations showed that the data obtained with agonists were consistent with these compounds achieving agonism by stabilising the ternary complex. For inverse agonists, the simulations showed that the mechanism for spiperone may be to stabilise forms of the receptor uncoupled from G proteins. Methiothepin, however, probably does not alter the equilibrium distribution of different receptor species; rather, this inverse agonist may stabilise an inactive form of the receptor that can still couple to G protein.