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John D Schuetz - One of the best experts on this subject based on the ideXlab platform.
influence of multidrug resistance associated proteins on the excretion of the abcc1 imaging probe 6 bromo 7 11 c methylpurine in miceMolecular Imaging and Biology, 2019Co-Authors: Viktoria Zoufal, Severin Mairinger, Markus Krohn, Thomas Wanek, Thomas Filip, Michael Sauberer, Johann Stanek, Alexander Traxl, John D SchuetzAbstract:
Multidrug resistance-associated proteins (MRPs) mediate the hepatobiliary and renal excretion of many drugs and drug conjugates. The positron emission tomography (PET) tracer 6-bromo-7-[11C]methylpurine is rapidly converted in tissues by glutathione-S-transferases into its glutathione conjugate, and has been used to measure the activity of Abcc1 in the brain and the lungs of mice. Aim of this work was to investigate if the activity of MRPs in excretory organs can be measured with 6-bromo-7-[11C]methylpurine. We performed PET scans with 6-bromo-7-[11C]methylpurine in groups of wild-type, ABCC4(−/−) and Abcc1(−/−) mice, with and without pre-treatment with the prototypical MRP inhibitor MK571. 6-Bromo-7-[11C]methylpurine-derived radioactivity predominantly underwent renal excretion. In blood, MK571 treatment led to a significant increase in the AUC and a decrease in the elimination rate constant of radioactivity (kelimination,blood). In the kidneys, there were significant decreases in the rate constant for radioactivity uptake from the blood (kuptake,kidney), kelimination,kidney, and the rate constant for tubular secretion of radioactivity (kurine). Experiments in ABCC4(−/−) mice indicated that ABCC4 contributed to renal excretion of 6-bromo-7-[11C]methylpurine-derived radioactivity. Our data suggest that 6-bromo-7-[11C]methylpurine may be useful to assess the activity of MRPs in the kidneys as well as in other organs (brain, lungs), although further work is needed to identify the MRP subtypes involved in the disposition of 6-bromo-7-[11C]methylpurine-derived radioactivity.
Journal of Biological Chemistry, 2013Co-Authors: Satish Cheepala, Ju Bao, Deepa Nachagari, Daxi Sun, Yao Wang, Tao P Zhong, Anjaparavanda P Naren, Jie Zheng, John D SchuetzAbstract:
The ABC transporter ABCC4 is recognized as an ATP-dependent exporter of endogenous substances as well as an increasing variety of anionic chemotherapeutics. A loss-of-function variant of zebrafish ABCC4 was identified with a single amino acid substitution in the cytoplasmic loop T804M. Because this substituted amino acid is highly conserved among ABCC4 orthologs and is located in cytoplasmic loop 3 (CL3), we investigated the impact of this mutation on human and zebrafish ABCC4 expression. We demonstrate that zebrafish ABCC4 T804M or human ABCC4 T796M exhibit substantially reduced expression, coupled with impaired plasma membrane localization. To understand the molecular basis for the localization defect, we developed a homology model of zebrafish ABCC4. The homology model suggested that the bulky methionine substitution disrupted side-chain contacts. Molecular dynamic simulations of a fragment of human or zebrafish CL3 containing a methionine substitution indicated altered helicity coupled with reduced thermal stability. Trifluoroethanol challenge coupled with circular dichroism revealed that the methionine substitution disrupted the ability of this fragment of CL3 to readily form an α-helix. Furthermore, expression and plasma membrane localization of these mutant ABCC4/ABCC4 proteins are mostly rescued by growing cells at subphysiological temperatures. Because the cystic fibrosis transmembrane conductance regulator (ABCC7) is closely related to ABCC4, we extended this by engineering certain pathogenic CFTR-CL3 mutations, and we showed they destabilized human and zebrafish ABCC4. Altogether, our studies provide the first evidence for a conserved domain in CL3 of ABCC4 that is crucial in ensuring its proper plasma membrane localization.
increasing systemic exposure of methotrexate by active efflux mediated by multidrug resistance associated protein 3 mrp3 abcc3Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Yoshiaki Kitamura, John D Schuetz, Masakazu Hirouchi, Hiroyuki Kusuhara, Yuichi SugiyamaAbstract:
The aim of this study was to investigate the functional importance of multidrug resistance-associated protein (Mrp)3/ Abcc3 and Mrp4/ ABCC4 in the pharmacokinetics of methotrexate. Compared with the corresponding wild-type mice, the plasma concentrations of methotrexate given orally were similar in ABCC4 -/- mice and were significantly lower in Abcc3 -/- mice. Pharmacokinetic parameters related to hepatobiliary transport were determined under steady-state conditions in wild-type and Abcc3 -/- mice that were given a constant intravenous infusion of methotrexate. The biliary clearance, based on the plasma concentration, was 1.6-fold greater in Abcc3 -/- mice than in wild-type mice (23 and 15 ml/min/kg, respectively, P < 0.05). Because the basolateral uptake and canalicular efflux clearances of methotrexate were similar in wild-type and Abcc3 -/- mice, this result suggests that the basolateral efflux clearance of methotrexate is decreased in the liver of Abcc3 -/- mice. Furthermore, a lower fraction of absorption of methotrexate ( F a F g) was suggested in Abcc3 -/- mice (0.49 and 0.29 in wild-type and Abcc3 - / - mice, respectively). The mucosal-to-serosal transport rate of methotrexate, determined in vitro using everted sacs, was highest in the duodenum and was significantly decreased in Abcc3 -/- mice compared with wild-type mice. This is ascribed to the reduced intrinsic efflux clearance of methotrexate across the serosal membrane (22 and 5.3 μl/min/sac in wild-type and Abcc3 - / - mice, respectively, P < 0.05). These results suggest that Mrp3 mediates basolateral efflux of methotrexate in the liver and duodenum, thereby serving to increase systemic exposure, whereas Mrp4 is likely to play only a limited role in the systemic methotrexate exposure.
nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codonsHuman Molecular Genetics, 2003Co-Authors: Jatinder K Lamba, Jaana Tammur, Masashi Adachi, Daxi Sun, Erin G Schuetz, Rando Allikmets, John D SchuetzAbstract:
Drug transporters are an important part of the defense of cells against cytotoxic agents. One major group of transporters is known as multidrug resistance associated proteins (MRP; ABCC gene family). The MRPs belong to the ATP binding cassette transporter superfamily. One family member, ABCC4 (also known as MRP4) functions as a cellular efflux pump for anti-HIV drugs, such as 9-(2-phoshoenylmethoxyethyl) adenine and azido-thymidine-monophosphate, an antiviral nucleotide, ganciclovir-monophosphate, and anti-cancer agents such as thiopurines. We isolated a ABCC4 cDNA encoding a non-functional protein, owing to an insertion, and subsequently determined the ABCC4 gene structure. This analysis revealed that the insertion was attributed to two additional exons that would be predicted to produce premature termination codons (PTC) in ABCC4. The highly similar mouse ABCC4 gene also contained these exons, which were remarkable because their size and sequence identity were much higher than the overall similarity between these genes. Further, a comparison of human, monkey and rodent ABCC4 genes revealed that these same PTC-producing exons were also highly conserved in evolution. As all the ABCC4 mRNA containing these PTC exons might produce nonsense mRNA, we further tested the hypothesis that these mRNAs were targets of nonsense-mediated mRNA decay (NMD). Protein synthesis inhibition selectively stabilized PTC containing ABCC4 transcripts in human, monkey and rodent cell lines. Moreover, the amount of PTC-containing ABCC4 transcripts was critically dependent upon protein synthesis, as removal of the inhibitor dramatically decreased expression, which correlated with the resumption of protein synthesis. These are the first studies to indicate that the highly conserved PTC exons of the ABCC4 gene may dictate its expression.
two new genes from the human atp binding cassette transporter superfamily abcc11 and abcc12 tandemly duplicated on chromosome 16q12Gene, 2001Co-Authors: Jaana Tammur, John D Schuetz, Catherine Prades, Isabelle Arnould, Andrey Rzhetsky, Amy Hutchinson, Masashi Adachi, Kathryn J Swoboda, Louis J Ptacek, Marie RosierAbstract:
Abstract Several years ago, we initiated a long-term project of cloning new human ATP-binding cassette (ABC) transporters and linking them to various disease phenotypes. As one of the results of this project, we present two new members of the human ABCC subfamily, ABCC11 and ABCC12. These two new human ABC transporters were fully characterized and mapped to the human chromosome 16q12. With the addition of these two genes, the complete human ABCC subfamily has 12 identified members (ABCC1–12), nine from the multidrug resistance-like subgroup, two from the sulfonylurea receptor subgroup, and the CFTR gene. Phylogenetic analysis determined that ABCC11 and ABCC12 are derived by duplication, and are most closely related to the ABCC5 gene. Genetic variation in some ABCC subfamily members is associated with human inherited diseases, including cystic fibrosis (CFTR/ABCC7), Dubin–Johnson syndrome (ABCC2), pseudoxanthoma elasticum (ABCC6) and familial persistent hyperinsulinemic hypoglycemia of infancy (ABCC8). Since ABCC11 and ABCC12 were mapped to a region harboring gene(s) for paroxysmal kinesigenic choreoathetosis, the two genes represent positional candidates for this disorder.
Jeremy A. Hirota - One of the best experts on this subject based on the ideXlab platform.
interactions between ABCC4 mrp4 and abcc7 cftr in human airway epithelial cells in lung health and diseaseThe International Journal of Biochemistry & Cell Biology, 2021Co-Authors: Jenny P Nguyen, Yechan Kim, Quynh T Cao, Jeremy A. HirotaAbstract:
ATP binding cassette (ABC) transporters are present in all three domains of life - Archaea, Bacteria, and Eukarya. The conserved nature is a testament to the importance of these transporters in regulating endogenous and exogenous substrates required for life to exist. In humans, 49 ABC transporters have been identified to date with broad expression in different lung cell types with multiple transporter family members contributing to lung health and disease. The ABC transporter most commonly known to be linked to lung pathology is ABCC7, also known as cystic fibrosis transmembrane conductance regulator - CFTR. Closely related to the CFTR genomic sequence is ABCC4/multi-drug resistance protein-4. Genomic proximity is shared with physical proximity, with ABCC4 and CFTR physically coupled in cell membrane microenvironments of epithelial cells to orchestrate functional consequences of cyclic-adenosine monophosphate (cAMP)-dependent second messenger signaling and extracellular transport of endogenous and exogenous substrates. The present concise review summarizes the emerging data defining a role of the (ABCC7/CFTR)-ABCC4 macromolecular complex in human airway epithelial cells as a physiologically important pathway capable of impacting endogenous and exogenous mediator transport and ion transport in both lung health and disease.
the impact of cigarette smoke exposure copd or asthma status on abc transporter gene expression in human airway epithelial cellsScientific Reports, 2019Co-Authors: Jennifer A Aguiar, Andrea Tamminga, Ryan D Huff, Jenny P Nguyen, Anna Dvorkingheva, Briallen Lobb, Martin R Stampfli, Andrew C. Doxey, Jeremy A. HirotaAbstract:
ABC transporters are conserved in prokaryotes and eukaryotes, with humans expressing 48 transporters divided into 7 classes (ABCA, ABCB, ABCC, ABCD, ABDE, ABCF, and ABCG). Throughout the human body, ABC transporters regulate cAMP levels, chloride secretion, lipid transport, and anti-oxidant responses. We used a bioinformatic approach complemented with in vitro experimental methods for validation of the 48 known human ABC transporters in airway epithelial cells using bronchial epithelial cell gene expression datasets available in NCBI GEO from well-characterized patient populations of healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma, with validation performed in Calu-3 airway epithelial cells. Gene expression data demonstrate that ABC transporters are variably expressed in epithelial cells from different airway generations, regulated by cigarette smoke exposure (ABCA13, ABCB6, ABCC1, and ABCC3), and differentially expressed in individuals with COPD and asthma (ABCA13, ABCC1, ABCC2, ABCC9). An in vitro cell culture model of cigarette smoke exposure was able to recapitulate select observed in situ changes. Our work highlights select ABC transporter candidates of interest and a relevant in vitro model that will enable a deeper understanding of the contribution of ABC transporters in the respiratory mucosa in lung health and disease.
Theresa M C Tan - One of the best experts on this subject based on the ideXlab platform.
The International Journal of Biochemistry & Cell Biology, 2004Co-Authors: Jing Bai, Liqi Lai, Hui Ching Yeo, Boon Cher Goh, Theresa M C TanAbstract:
Abstract Multidrug resistance proteins (MRPs) are ATP-dependent export pumps that mediate the export of organic anions. ABCC1 (MRP1), ABCC2 (MRP2) and ABCC3 (MRP3) are all able to facilitate the efflux of anionic conjugates including glutathione (GSH), glucuronide and sulfate conjugates of xenobiotics and endogenous molecules. Earlier studies showed that ABCC4 functions as an ATP-driven export pump for cyclic AMP and cyclic GMP, as well as estradiol-17-β- d -glucuronide. However, it was unclear if other conjugated metabolites can be transported by ABCC4. Hence in this study, a fluorescent substrate, bimane-glutathione (bimane-GS) was used to further examine the transport activity of ABCC4. Using cells stably overexpressing ABCC4, this study shows that ABCC4 can facilitate the efflux of the glutathione conjugate, bimane-glutathione. Bimane-glutathione efflux increased with time and >85% of the conjugate was exported after 15 min. This transport was abolished in the presence of 2.5 μM carbonylcyanide m-chlorophenylhydrasone (CCCP), an uncoupler of oxidative phosphorylation. Inhibition was also observed with known inhibitors of MRP transporters including benzbromarone, verapamil and indomethacin. In addition, 100 μM methotrexate, an ABCC4 substrate or 100 μM 6-thioguanine (6-TG), a compound whose monophosphate metabolite is an ABCC4 substrate, reduced efflux by >40%. A concentration-dependent inhibition of bimane-glutathione efflux was observed with 1-chloro-2,4-dinitrobenzene (CDNB) which is metabolized intracellularly to the glutathione conjugate, 2,4-dinitrophenyl-glutathione (DNP-GS). The determination that ABCC4 can mediate the transport of glucuronide and glutathione conjugates indicates that ABCC4 may play a role in the cellular extrusion of Phase II detoxification metabolites.
role of glutathione in the multidrug resistance protein 4 mrp4 ABCC4 mediated efflux of camp and resistance to purine analoguesBiochemical Journal, 2002Co-Authors: Liqi Lai, Theresa M C TanAbstract:
Multidrug resistance protein 4 (MRP4/ABCC4) is a member of the MRP subfamily, which in turn is a member of the superfamily of ATP-binding-cassette (ABC) transporters. Within the MRP subfamily, ABCC4,ABCC5 (MRP5), ABCC11 (MRP8) and ABCC12 (MRP9) have similar predicted membrane topologies. All lack the additional transmembrane domain, TMD(0), which is present in the other MRPs. Using cells stably overexpressing ABCC4, this study shows that ABCC4 exports GSH. ABCC4 also facilitates the efflux of cAMP. Depletion of intracellular GSH with DL-buthionine-(S,R)-sulphoximine led to decreased export of cAMP and a corresponding increase in intracellular cAMP was observed. ABCC4 also mediates resistance to purine analogues 9-(2-phosphonylmethoxyethyl)-adenine and 6-thioguanine. This resistance can be reversed by the presence of DL-buthionine-(S,R)-sulphoximine. We conclude that as well as nucleotide and nucleoside analogues, ABCC4 can mediate the export of GSH. In addition, GSH plays an important role in the function of ABCC4. Depletion of intracellular GSH adversely affects the export of cAMP by ABCC4. Resistance to nucleoside analogues is also adversely affected by depletion of cellular GSH.
Dietrich Keppler - One of the best experts on this subject based on the ideXlab platform.
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Maria Rius, Johanna Hummeleisenbeiss, Dietrich KepplerAbstract:
The proinflammatory mediators leukotriene (LT) B(4) and LTC(4) must be transported out of cells before they can interact with LT receptors. Previously, we identified the multidrug resistance protein ABCC1 (MRP1) as an efflux pump for LTC(4). However, the molecular basis for the efflux of LTB(4) was unknown. Here, we demonstrate that human ABCC4 mediates the ATP-dependent efflux of LTB(4) in the presence of reduced glutathione (GSH), whereby the latter can be replaced by S-methyl GSH. Transport studies were performed with inside-out membrane vesicles from V79 fibroblasts and Sf9 insect cells that contained recombinant ABCC4, with vesicles from human platelets and myelomonocytic U937 cells, which were rich in endogenous ABCC4, but ABCC1 was below detectability. Moreover, human polymorphonuclear leukocytes contained ABCC4. K(m) values for LTB(4) were 5.2 muM with vesicles from fibroblasts and 5.6 muM with vesicles from platelets. ABCC4, with its broad substrate specificity, also functioned as an ATP-dependent efflux pump for LTC(4) with a K(m) of 0.13 muM in vesicles from fibroblasts and 0.32 muM in vesicles from platelets. However, GSH was not required for the transport of this glutathionylated leukotriene. The transport of LTC(4) by ABCC4 explains its release from platelets during transcellular synthesis. ATP-dependent transport of LTB(4) and LTC(4) by ABCC4 was inhibited by several organic anions, including S-decyl GSH, sulindac sulfide, and by the LTD(4) receptor antagonists montelukast and 3-(((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-((3-dimethyl-amino-3-oxopropyl)-thio)-methyl)thio)propanoic acid (MK571). Thus, as an efflux pump for the proinflammatory mediators LTB(4) and LTC(4), ABCC4 may represent a novel target for anti-inflammatory therapies.
Pflugers Archiv European Journal of Physiology, 2007Co-Authors: Anne T Nies, Dietrich KepplerAbstract:
ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C(4), bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome.
ABCC Drug Efflux Pumps and Organic Anion Uptake Transporters in Human Gliomas and the Blood-Tumor BarrierCancer Research, 2005Co-Authors: Holger Bronger, Dietrich Keppler, Jörg König, Kathrin Kopplow, Hans-herbert Steiner, Rezvan Ahmadi, Christel Herold-mende, Anne T NiesAbstract:
Delivery of therapeutic agents to the brain and its neoplasms depends on the presence of membrane transport proteins in the blood-brain barrier and in the target cells. The cellular and subcellular localization of these membrane transporters determines the drug accessibility to the brain and its tumors. We therefore analyzed the expression and localization of six members of the multidrug resistance protein family of ATP-dependent efflux pumps (ABCC1-ABCC6, formerly MRP1-MRP6) and of six organic anion uptake transporters (OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, and OATP4A1) in 61 human glioma specimens of different histologic subtypes. Real-time PCRs indicated expressions of ABCC1, ABCC3, ABCC4, and ABCC5. In addition, we detected expressions of the OATP uptake transporter genes SLCO1A2, SLCO1C1, SLCO2B1, and SLCO4A1. At the protein level, however, only OATP1A2 and OATP2B1 were detectable by immunofluorescence microscopy in the luminal membrane of endothelial cells forming the blood-brain barrier and the blood-tumor barrier, but not in the glioma cells. ABCC4 and ABCC5 proteins were the major ABCC subfamily members in gliomas, localized both at the luminal side of the endothelial cells and in the glioma cells of astrocytic tumors and in the astrocytic portions of oligoastrocytomas. These results indicate that expression of ABCC4 and ABCC5 is associated with an astrocytic phenotype, in accordance with their expression in astrocytes and with the higher chemoresistance of astrocytic tumors as compared with oligodendrogliomas. Our data provide a basis for the assessment of the role of uptake transporters and efflux pumps in the accessibility of human gliomas for chemotherapeutic agents.
Heyo K. Kroemer - One of the best experts on this subject based on the ideXlab platform.
Role of the ABC-transporters ABCC4, ABCC5 and ABCC11 in response to chemotherapy in adult patients with acute myeloid leukemiaCancer Research, 2005Co-Authors: Christoph A. Ritter, Kathleen Kock, Gabriele Jedlitschky, James F. Beck, Gerhard Ehninger, Heyo K. Kroemer, Markus SchaichAbstract:
6169 Resistance to chemotherapeutic drugs is a major factor limiting a successful therapy. One proposed mechanism for treatment failure in patients with acute myeloid leukemia (AML) is the efflux of cytostatics. The multidrug resistance-associated proteins ABCC4, ABCC5 and ABCC11 have the ability to transport cyclic nucleotides and anti-cancer nucleoside analogs. These substances are particularly valuable for the treatment of AML, which is the most common form of leukemia in adults. Therefore we examined the clinical relevance of ABCC4, ABCC5 and ABCC11 by analyzing their mRNA expression levels in pre-treatment leukemic blast cells of the bone marrow of 50 newly diagnosed AML-patients participating in the SHG-AML-96 study. mRNA expression levels were investigated by quantitative TaqMan Real-time PCR and normalized to 18S mRNA expression. The median relative mRNA expression levels of the patient probes were different between the three examined genes (28.8 (ABCC4), 63.7 (ABCC5), 0.34 (ABCC11)). There was no significant association with age, white blood cell count, frequency of blast cells in bone marrow and P-gp mRNA level, but patients with the French-American-British (FAB) subtype M1 showed a higher mRNA expression of all genes examined (P ABCC4 =0.002; P ABCC5 =0.007; P ABCC11 =0.004). For ABCC4 and ABCC5 no significant association was found for complete remission rate and overall survival. However, Kaplan-Meyer statistics and Log-rank test suggest that despite its low mRNA expression ABCC11 has a negative influence on overall survival with a 5 year probability of survival of 28% for patients with low and only 8% for patients with high ABCC11 expression (P=0.03). As complete remission rate was not affected this was mainly due to a higher relapse rate in high ABCC11 expressing patients. In conclusion, ABCC11 expression seems to be a new promising predictor for treatment outcome in adult AML.
Cellular export of drugs and signaling molecules by the ATP-binding cassette transporters MRP4 (ABCC4) and MRP5 (ABCC5).Drug Metabolism Reviews, 2005Co-Authors: Christoph A. Ritter, Kathleen Kock, Gabriele Jedlitschky, Heyo K. Kroemer, Henriette E. Meyer Zu Schwabedissen, Markus GrubeAbstract:
Like other members of the multidrug resistance protein (MRP)/ABCC subfamily of ATP-binding cassette transporters, MRP4 (ABCC4) and MRP5 (ABCC5) are organic anion transporters. They have, however, the outstanding ability to transport nucleotides and nucleotide analogs. In vitro experiments using drug-selected or -transfected cells indicated that these transport proteins, when overexpressed, can lower the intracellular concentration of nucleoside/nucleotide analogs, such as the antiviral compounds PMEA (9-(2-phosphonylmethoxyethyl)adenine) or ganciclovir, and of anticancer nucleobase analogs, such as 6-mercaptopurine, after their conversion into the respective nucleotides. This may lead to an impaired ability of these compounds to inhibit virus replication or cell proliferation. It remains to be tested whether antiviral or anticancer chemotherapy based on nucleobase, nucleoside, or nucleotide precursors can be modulated by inhibition of MRP4 and MRP5. MRP4 also seems to be able to mediate the transport of conjugated steroids, prostaglandins, and glutathione. Furthermore, cyclic nucleotides (cyclic adenosine monophosphate and cyclic guanine monophosphate) are exported from cells by MRP4 and MRP5. This may modulate the intracellular concentration of these important mediators, besides the action of phosphodiesterases, as well as provide extracellular nucleotides for a possible paracrine action. In this line, tissue distribution and subcellular localization of MRP4 and MRP5 specifically in smooth muscle cells (MRP5), platelet-dense granules (MRP4), and nervous cells (MRP4 and MRP5), besides the capillary endothelium, point not only to a possible function of these transporters as exporters in cellular defense, but also to a physiological function in signaling processes.