Pharmaceutical approaches using prostanoid receptor knockout mice

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In order to clarify the molecular actions of prostaglandins and the development of new drug on the basis of such molecular information, it needs to study the following two points ; 1. the structures and functions of prostanoid receptors, especially on the focus of the binding domain and functional domain relating to G protein activation, 2. analyzes of tissue specific expression of their receptors and of the phenotypic appearance of their receptor knock-out mice. In the first project, we have obtained the following results ; (1) we analyzed the prostanoid receptor-ligand interaction, and found that the Arg residue within 7th transmembrane domain is the binding site for the carboxylic acid of prostanoid. (2) In the point mutation of the EP3 receptor we obtained that the hydrogen bonding interation of agonists and carbonyl residue of EP3 agonists is sufficient for the functional activation. (3) This interaction is essential for the activation of Gs and Gq but not Gi in EP3D receptor. In the second project, (1) we have prepared some knock-out mice which are deficient in PGF (FP) receptor and EP2/EP4 receptors. (2) FP knock-out mice revealed the loss of delivery of growing fetus. The mechanism is supposed to be involved in the deficient of PGF action in the regression of corpus luteum. (3) We have been making EP2 and EP4 knock-out mice. EP4 knock-out mice has a severe phenotypic appearance, since they die during 1-2 days after birth because of the deficient function of vascular circulation. In future we like to focus our experimental point to reveal the specific action of local tissue circumstances.