{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed that PAQR7—a member of the progestin and adipoQ receptor (PAQR) family that possesses seven‐transmembrane domains—functions as a membrane progesterone receptor (often referred to as mPRα). PAQR7 binds progestins with high affinity and, much like classical G protein–coupled receptors, is directly coupled to inhibitory G proteins that down‐regulate adenylyl cyclase activity, thereby mediating rapid, non‐genomic progesterone signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn reproductive tissues, PAQR7 plays key roles in mediating progesterone’s rapid actions. For example, PAQR7 is expressed on human sperm membranes—particularly on the midpiece—and its abundance correlates with sperm motility, suggesting that this receptor facilitates progestin‐stimulated G protein activation and subsequent hyperactivation of sperm. In ovarian cancer cells, where classical nuclear progesterone receptors are absent or minimally expressed, PAQR7-dependent signaling modulates intracellular cAMP levels, activates MAP kinase pathways (including JNK1/2), and influences pro-apoptotic markers, thereby implicating PAQR7 in anti-tumorigenic and anti-apoptotic processes within the ovary."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond reproductive tissues, PAQR7 is emerging as a mediator of rapid progesterone actions in diverse cell types. In epidermal melanocytes—cells that lack classical estrogen or nuclear progesterone receptors—PAQR7, acting in concert with the G protein–coupled estrogen receptor, contributes to the reciprocal regulation of melanin synthesis by progesterone. Similar non-genomic progesterone effects involving PAQR7 have been observed in glioma cells. In vascular smooth muscle cells, activation of PAQR7 reduces calcium influx, thereby promoting cell relaxation through modulation of Rho/ROCK, MAPK, and Akt signaling pathways. Moreover, in models of nerve repair and neuroprotection—including Schwann cell–like adipose stem cells and neuronal cell lines—PAQR7 activation enhances cell migration, differentiation, neurotrophin (e.g., BDNF and IGF-2) release, and neurite outgrowth, suggesting promising regenerative roles."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMethodological advances have also deepened our understanding of PAQR7. For example, the development of novel binding assays using graphene quantum dots has enabled the detailed evaluation of ligand–receptor interactions for PAQR7, facilitating high-throughput screening strategies for potential drug discovery applications. Furthermore, emerging insights into the receptor’s structural topology, post-translational modifications, and trafficking to the plasma membrane suggest complex regulatory mechanisms that underpin its multifaceted roles in both reproductive and non-reproductive tissues. Together, these findings position PAQR7 as a critical mediator of membrane-initiated progesterone signaling and a potential therapeutic target in contexts such as ovarian function, neurodegeneration, and peripheral nerve regeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Peter Thomas, Y Pang, J Dong, et al. 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