3.A.1.208.7
MRP4 (MDR4; ABCC4); exporter of cyclic nucleotides (cAMP, cGMP, cUMP) and other nucleotide analogues, particularly purine analogues, methotrexate, adefovir (antiviral), bile acids, prostaglandins E1 and E2, reduced folates, 9-(2-phosphonylmethyoxyethyl)adenine, leukotrienes, estradiol 17-β-D-glucuronide) and drug sulfate conjugates (inhibited by nonsteroidal antiinflammatory drugs Reid et al., 2003; Rius et al., 2008)). When overexpressed, it can lower the intracellular concentration of nucleoside/nucleotide analogs, such as the antiviral compounds PMEA (9-(2-phosphonylmethoxyethyl)adenine), adefovir, or ganciclovir (Nigam 2015), and of anticancer nucleobase analogs, such as 6-mercaptopurine, after their conversion into the respective nucleotides. MRP4 interacts directly with CFTR (3.A.1.202.1) to control Cl^- secretion (Li et al., 2007). It also functions in urate elimination across the renal tubule apical membrane (Prestin et al. 2014). Thus, MRP4 is a broad specificity organic anion exporter (Ritter et al., 2005). MRP4 and CFTR together function in the regulation of cAMP and beta-adrenergic contraction in cardiac myocytes (Sellers et al., 2012). Amino acid changes can alter the uptake of drugs such as 6-mercaptopurine (6-MP) and 9-(2-phosphonyl methoxyethyl) adenine (PMEA) (Janke et al. 2008).  Positions of L1 (the linker between the two halves of the exporter), L0 (the N-terminal domain), and the zipper helices (between the two NBDs) have been suggested (Chantemargue et al. 2018). ABCC4 exports proinflammatory molecules including leukotriene, prostaglandin and sphingosine-1-phosphate across the plasma membrane. These metabolites play roles in asthma (Palikhe et al. 2017). Symmetrical 1,4-dihydropyridines are inhibitors of the MRP4 Efflux Pump and can be used for anticancer therapy (Döring et al. 2020). MRP4 contributes to platelet activation by extruding endogenous molecules responsible for their activation and accumulation and may also export various drugs (Angelis et al. 2021). Symmetrical cage compounds are inhibitors of the symmetrical MRP4-efflux pump for anticancer therapy (Kreutzer et al. 2021). The ABCC4 gene is associated with pyometra in dogs (Arendt et al. 2021) and Chronic Myeloid Leukemia in humans (Monte et al. 2021). Cellular uptake of and transport mechanisms for 6-mercaptopurine nanomedicines (6-MPNs) for enhanced oral bioavailability have been described (Zou et al. 2023), and MRP4 plays a significant role. ABCC4 is a prostaglandin E2 efflux transporter in the ovarian follicle and is a mediator of ovulation with a potential non-hormonal contraceptive target (Yerushalmi et al. 2023). Thus, the ABCC4 inhibitor probenecid blocks ovulation and affects key ovulatory genes in female mice in vivo. The ATP-bound inward-open conformation of ABCC4 revealed asymmetric ATP binding for substrate transport (Zhu et al. 2024). ABCC4 is found in the intestine, kidney and liver (Wang et al. 2024).  Enhanced platelet sensitization is accompanied by increased expression of MRP4 and elevated plasma S1P levels in mild COVID-19 convalescents (Tolksdorf et al. 2024). ABCC4 and CFTR interact in human airway epithelial cells in lung health and disease (Nguyen et al. 2021). .