| MRP4/ABCC4 is a member of the ABCC subfamily of ATP‑binding cassette transporters and functions as an efflux pump for a broad spectrum of endogenous signaling molecules and xenobiotic anions, using ATP hydrolysis at its two nucleotide-binding domains to drive vectorial transport across the plasma membrane. The polytopic architecture comprises two transmembrane domains forming the substrate translocation pathway and two cytosolic nucleotide-binding domains with Walker and signature motifs that couple ATP binding and hydrolysis to conformational rearrangements of the transport cavity, supporting alternating access of substrates to intracellular and extracellular compartments. MRP4 exports cyclic nucleotides such as cAMP and cGMP, prostaglandins, and diverse nucleoside analogues, so its activity directly shapes intracellular second-messenger pools and controls the extracellular levels of lipid mediators that interact with G protein–coupled receptors, linking transporter function to downstream PKA/PKG signaling and prostanoid receptor pathways. In neuroblastoma cells, ABCC4 expression is transcriptionally driven by MYCN and other Myc family oncoproteins, and high transporter levels correlate with aggressive clinical behavior, reflecting the combined impact of efflux of chemotherapeutic agents including topoisomerase I poisons and modulation of endogenous signaling molecules that influence proliferation and survival programs. MRP4 localizes mainly to the plasma membrane of tumor cells and mediates outward transport of irinotecan metabolites and other cytotoxic drugs used in solid tumor regimens, thereby reducing intracellular drug accumulation and contributing to multidrug resistance phenotypes that complicate treatment. MRP4-dependent extrusion of cyclic nucleotides and prostaglandins affects cAMP and prostanoid gradients in the tumor microenvironment, altering paracrine communication, differentiation status, and responses to growth factors and cytokines. ABCC4 also transports cyclic nucleotides in dendritic cells and vascular cells, where its activity influences cell migration, immune activation, and vascular tone, providing a mechanistic basis for links between ABCC4 genetic variants and susceptibility to Kawasaki disease and other cardiovascular traits. |
