Membrane progesterone receptors and progesterone receptor membrane component 1 (mPRs/PGRMC1)

Membrane-associated progesterone receptors, primarily comprising the membrane progesterone receptor (mPR) family and progesterone receptor membrane component 1 (PGRMC1), are non-genomic receptors that mediate rapid cellular responses to progesterone. The mPR family (subtypes alpha, beta, gamma, delta, and epsilon) consists of seven-transmembrane proteins belonging to the PAQR family that signal through G-protein coupling to regulate cAMP and activate pro-survival pathways like PI3K/Akt and MAPK. PGRMC1 is a single-transmembrane protein with a cytochrome b5-like heme-binding domain that acts as a signaling adaptor and regulator of cytochrome P450 enzymes, influencing steroidogenesis and drug metabolism. These receptors are frequently overexpressed in various malignancies, including breast, ovarian, and lung cancers, where they promote tumor cell survival, chemoresistance, and metastasis. Beyond oncology, they play critical roles in reproductive physiology, such as oocyte maturation and sperm motility, and exhibit neuroprotective effects in the central nervous system. PGRMC1 also interacts with other membrane proteins like EGFR, stabilizing them at the cell surface and modulating their signaling. Therapeutic strategies targeting these receptors include selective agonists for neuroprotection and antagonists or inhibitors like AG-205 to sensitize cancer cells to treatment. Due to their involvement in drug metabolism and wide tissue distribution, targeting these receptors requires careful consideration of potential drug-drug interactions and off-target effects.

Other names

Membrane-associated progesterone receptorsNon-genomic progesterone receptorsPAQR familyMAPR familyPGRMC1mPR alphamPR betamPR gamma25-DxHPR6.6

Activation of G-protein signaling (Gi/Gs), modulation of adenylyl cyclase and cAMP levels, activation of PI3K/Akt and MAPK/ERK pathways, and regulation of cytochrome P450 enzyme activity and membrane receptor stability.