title: Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP.
abstract: The second messenger, cGMP, mediates a host of cellular responses to various stimuli, resulting in the regulation of many critical physiologic functions. The existence of specific cGMP transporters on the plasma membrane that participate in the regulation of cGMP levels has been suggested in a large number of studies. In this study, we identified a novel plasma membrane transporter for cGMP. In particular, we showed that hOAT2 (SLC22A7), a member of the solute carrier (SLC) superfamily, was a facilitative transporter for cGMP and other guanine nucleotides. hOAT2, which is ubiquitously expressed at high levels in many cell types, was previously thought to primarily transport organic anions. Among purine and pyrimidine nucleobases, nucleosides, and nucleotides, hOAT2 showed the greatest preference for cGMP, which transported cGMP with a K(m) value of 88 +/- 11 muM and exhibited between 50- and 100-fold enhanced uptake over control cells. Our data revealed that hOAT2 is a bidirectional facilitative transporter that can control both intracellular and extracellular levels of cGMP. In addition, we observed that a common alternatively spliced variant of hOAT2 demonstrated a complete loss of transport function as a result of a low expression level on the plasma membrane. We conclude that hOAT2 is a highly efficient, facilitative transporter of cGMP and may be involved in cGMP signaling in many tissues. Our study suggests that hOAT2 represents a potential new drug target for regulating cGMP levels.
authors.affiliation: Department of Biopharmaceutical Sciences, 1550 4th Street, RH584, Box 2911, University of California, San Francisco, CA 94158-2911, USA. kathy.giacomini@ucsf.edu
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Cropp
authors.forename: Takafumi
authors.initials: T
authors.lastname: Komori
authors.forename: James E
authors.initials: JE
authors.lastname: Shima
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Urban
authors.forename: Sook Wah
authors.initials: SW
authors.lastname: Yee
authors.forename: Swati S
authors.initials: SS
authors.lastname: More
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000596:Amino Acids; D001692:Biological Transport; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism*; D003849:Deoxyguanosine / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection
chemical_list: D000596:Amino Acids; D009705:Nucleosides; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C490280:SLC22A7 protein, human; D003849:Deoxyguanosine; D006152:Cyclic GMP