We examined the contribution of Ser203 of the human β2-adrenoceptor (β2-AR) to the interaction with isoprenaline. The affinity of (-)-isoprenaline was reduced by substitution of an alanine for Ser203, as well as for Ser204 and Ser207. An (-)-isoprenaline derivative with only one hydroxyl group, at the meta-position, showed reduced affinity for wild-type β2-AR and S207A-β2-AR and even lower affinities for S203A-β2-AR and S204A-β2-AR. By contrast, an (-)-isoprenaline derivative with only a para-hydroxyl group showed reduced affinity for wild-type β2-AR but the serine to alanine mutations did not cause further decreases. The EC50 value for cyclic AMP generation in response to (-)-isoprenaline was increased, by about 120 fold, for each alanine-substituted β2-AR mutant. These results suggest that Ser203 of the human β2-AR is important for both ligand binding and receptor activation.
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