Four prostaglandin (PG)E(2) receptors have been described, termed E-series prostaglandin receptors (EP(1)-EP(4)), that can be further subclassified as low-affinity (EP(1) and EP(2)) or high-affinity (EP(3) and EP(4)) receptors. Activation of the low-affinity PGE(2) receptors is likely to be important in mediating the actions of the high levels of PGE(2) found in various pathologic processes. The pattern of expression of these receptors in epidermis, however, is unknown. We therefore examined the immunolocalization of the EP(1) and EP(2) receptors in human epidermis. The EP(1) and EP(2) receptors demonstrated both plasma membrane and perinuclear or nuclear staining within the basal and spinous layers. Within the granular layer, both receptors were expressed in the cytoplasm with a grainy or granular appearance. The major differences were that the EP(2) receptor demonstrated a zone of decreased to absent plasma membrane staining in the superficial spinous layer and only scattered cellular staining within the granular layer. In contrast, the EP(1) receptor was prominently expressed throughout the stratum granulosum and the plasma membrane staining pattern was seen throughout the spinous layer. In cultured primary human keratinocytes, we also verified the presence of functional EP(1) receptor coupled to intracellular calcium mobilization and EP(2) receptor coupled to cAMP production.