Emerging roles of progesterone receptor membrane components in pregnancy and parturition

Progesterone receptor membrane components 1 and 2 (PGRMC1 and PGRMC2) are single-pass proteins that function as multi-ligand regulators. They integrate signals from progesterone (P4), heme, and cytochrome P450 enzymes (CYPs). Accumulating evidence implicates PGRMCs in non-genomic progesterone signaling in cell, cancer, and reproductive biology. Heme binding (through their heme binding domain) and cytochrome P450 enzymes (CYPs) binding provide distinct functional roles for PGRMCs in various cells under specific cellular environment. In reproductive tissues, multiple functional roles have been reported for both PGRMC1 and PGRMC2 in both maternal and fetal organs. Ambiguity still exists about their independent functional role and contributions in pregnancy maintenance or initiation of parturition. Collectively, PGRMC1 and PGRMC2 act in complementary ways to regulate heme biology, metabolism, and P4-responsive signaling in gestational tissues. With the growing interest in PGRMC's role in pregnancy associated tissues, we provide a comprehensive narrative of PGRMCs through this review to facilitate future research and stimulate continued discussions.