Candidates for membrane progestin receptors--past approaches and future challenges

Progestins have a broad range of functions in reproductive biology. Many rapid nongenomic actions of progestins have been identified, including induction of oocyte maturation, modulation of reproductive signaling in the brain, rapid activation of breast cancer cell signaling, induction of the acrosomal reaction and hypermotility in mammalian sperm. Currently, there are three receptor candidates for mediating rapid progestin actions: (1) membrane progestin receptors (mPRs); (2) progestin receptor membrane components (PGRMCs); and (3) nuclear progestin receptors (nPRs). The recently-described mPR family of proteins has seven integral transmembrane domains and mediates signaling via G-protein coupled pathways. The PGRMCs have a single transmembrane with putative Src homology domains for potential activation of second messengers. The classical nPRs, in addition to having well defined transcriptional activity, can also mediate rapid activation of intracellular signaling pathways. However, details of the mechanisms by which these three classes of progestin receptors mediate rapid intracellular signaling and their subcellular localization remain unclear. In addition, mPRs, nPRs and PGRMCs exhibit overlapping expression and functions in multiple tissues, implying potential interactions during oocyte maturation, parturition, and breast cancer signaling in individual cells. However, the overwhelming majority of studies to date have focused on the functions of one of these groups of receptors in isolation. This review will summarize recent findings on the three major progestin receptor candidates, emphasizing the different approaches used, some experimental pitfalls, and current controversies. We will also review evidence for the involvement of mPRs and nPRs in one of the most well-characterized nongenomic steroid actions in basal vertebrates, oocyte maturation, and conclude by suggesting some future areas of research. Clarification of the controversies surrounding the identities and localization of membrane progestin receptors may help direct future research that could advance our understanding of rapid actions of steroids.