Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding the hepatic efflux transporter ABCC6. Elegant experiments performed by Uitto and co-workers have demonstrated that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver[1,2]. Why absence of this factor results in PXE has for long remained a mystery. We have recently shown that medium from HEK293 cells overexpressing ABCC6 potently inhibits mineralization in vitro, whereas medium of HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, predominantly ATP. Extracellularly, ectonucleotidases hydrolysed the excreted ATP into AMP and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization that plays a crucial role in several mineralization disorders similar to PXE[3]. In liver perfusion experiments we found that hepatocytes also release ATP in an Abcc6-dependent manner. Remarkably, within the liver vasculature released ATP was quantitatively converted into AMP and PPi. In Abcc6-/- mice this resulted in plasma PPi levels that were less than 40% of those found in wildtype mice. The importance of our findings was further demonstrated in in a group of Dutch PXE patients with known ABCC6 mutations. PXE patients had plasma PPi concentrations that were 2.5 times lower than those found in healthy individuals. These data not only explain why PXE patients suffer from an ectopic mineralization phenotype, but also provide new leads for the treatment of this currently intractable disease. Our data now firmly link ABCC6 to the release of ATP from (liver)cells. This is a peculiar function for an ABC transporter: Most ABC proteins use the energy released by intracellular ATP hydrolysis to transport specific substrates across membranes, often against steep concentration gradients[4]. Several ABC proteins have been shown to transport cyclic nucleotides[5-7] and nucleoside analogues[8,9], but not ATP. Completely unclear is how ABCC6 mediates ATP release. We therefore decided to study ABCC6-mediated ATP release in more detail and found that this process has intriguing electrophysiological aspects, which I will discuss in more detail during my presentation. 1. Jiang Q, Endo M, Dibra F, Wang K, Uitto J (2009) Pseudoxanthoma elasticum is a metabolic disease. J Investig Dermatol 129: 348-354. doi:10.1038/jid.2008.212. 2. Jiang Q, Oldenburg R, Otsuru S, Grand-Pierre AE, Horwitz EM, et al. (2010) Parabiotic Heterogenetic Pairing of Abcc6−/−/Rag1−/− Mice and Their Wild-Type Counterparts Halts Ectopic Mineralization in a Murine Model of Pseudoxanthoma Elasticum. The American Journal of Pathology 176: 1855-1862. doi:10.2353/ajpath.2010.090983. 3. Nitschke Y, Rutsch F (2012) Genetics in Arterial Calcification: Lessons Learned From Rare Diseases. Trends Cardiovas Med 22: 145-149. doi:10.1016/j.tcm.2012.07.011. 4. Borst P, Oude Elferink R (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71: 537-592. doi:10.1146/annurev.biochem.71.102301.093055. 5. Borst P, de Wolf C, van de Wetering K (2006) Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Arch 453: 661-673. doi:10.1007/s00424-006-0054-9. 6. de Wolf CJF, Yamaguchi H, Van der Heijden I, Wielinga PR, Hundscheid SL, et al. (2006) cGMP transport by vesicles from human and mouse erythrocytes. FEBS Journal 274: 439-450. doi:10.1111/j.1742-4658.2006.05591.x. 7. Russel F, Koenderink J, Masereeuw R (2008) Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci 29: 200-207. doi:10.1016/j.tips.2008.01.006. 8. Wielinga PR, Reid G, Challa EE, van der Heijden I, van Deemter L, et al. (2002) Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Mol Pharmacol 62: 1321-1331. 9. Reid G, Wielinga P, Zelcer N, de Haas M, Van Deemter L, et al. (2003) Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol 63: 1094-1103.