The molecular biology and ocular distribution of prostanoid receptors

Enormous progress has been made in the characterization of prostanoid receptors during the past five years. Molecular biological studies have enabled structural identification of all the human prostanoid receptors that had been proposed according to pharmacological criteria. The pharmacological classification proposed different receptor subtypes for prostaglandins D2, E2, F2 alpha, I2 and thromboxane A2 which were termed DP, EP, FP, IP and TP, respectively. Further subdivision for only the EP receptor has been reported and EP1, EP2, EP3, and EP4 subtypes have been unequivocally identified. The molecular structure of all prostanoid receptors is typical of that for G protein-coupled receptors and consists of seven alpha-helical transmembrane domains, three extracellular loops and an amino terminus, and three intracellular loops and a carboxyl terminus. Interestingly, mRNA alternative splice variants of the carboxyl termini have been found to determine G protein interactions for the EP3 receptor. Application of molecular biological techniques is beginning to make an impact in ocular research, where precise localization of receptors is difficult by more traditional methods because of the diminutive size of most ocular tissues. In situ hybridization and immunohistochemical studies using antibodies against the cloned human FP receptor have already suggested an unexpectedly wide distribution in the monkey eye. Transgenic studies involving FP receptor knock-out animals may provide future insight into the role of this receptor in glaucoma. However, since prostaglandins are extraordinarily effective in reducing intraocular pressure, it follows that traditional physiological and pharmacological studies retain a key role in glaucoma research. Studies in perfused human anterior segment organ culture have revealed that although prostaglandin F2 alpha does not facilitate trabecular aqueous humor outflow, prostaglandin E1 does increase trabecular outflow. Thus, different prostanoids may lower intraocular pressure by distinctly different mechanisms of action. Recent studies also indicate that prostanoids may exert a beneficial effect on retinal blood perfusion and may even act as neuroprotective agents.