THE MOLECULAR-BIOLOGY AND OCULAR DISTRIBUTION OF PROSTANOID RECEPTORS

Enormous progress has beer made in the characterization of prostanoid receptors during the past five years Molecular biological studies have enabled structural identification of all the human-prostanoid recepto rs that had beer proposed according to pharmacological criteria. The p harmacological classification proposed different receptor subtypes for prostaglandins D-2, E(2), F-2 alpha, I-2 and thromboxane A(2) which w ere termed DP, EP, FP, IP and TP, respectively. Further subdivision fo r only the EP receptor has been reported and EP(1), EP(2), EP(3), and EP(4), subtypes hare been unequivocally identified. The molecular stru cture of an prostanoid receptors is typical of that for G protein-coup led receptors and consists of seven alpha-helical transmembrane domain s, three extracellular loops and an amino terminus and three intracell ular loops and a carboxyl terminus. Interestingly, mRNA alternative sp lice variants of the carboxyl termini have been found to determine G p rotein interactions for the EP(3) receptor Application of molecular bi ological techniques is beginning to make an impact in ocular research where precise localization of receptors is difficult by more tradition al methods because of the diminutive size of most ocular tissues. In s itu hybridization aad immunohistochemical studies using antibodies aga inst the cloned human FP receptor have already suggested an unexpected ly wide distribution in the monkey eye Transgenic studies involving FP receptor knock-out animals may provide future insight into the role o f this receptor in glaucoma. However; since prostaglandins are extraor dinarily effective in reducing intraocular pressure, it follows that t raditional physiological and pharmacological studies retain a key role in glaucoma research. Studies in perfused human anterior segment orga n culture revealed that although prostaglandin F-2 alpha does not faci litate trabecular aqueous humor outflow, prostaglandin E(1) does incre ase trabecular outflow. Thus, different prostanoids may lower intraocu lar pressure by distinctly different mechanisms of action. Recent stud ies also indicate that prostanoids may exert a beneficial effect on re tinal blood perfusion and may even act as nanoprotective agents.