All cell functions ultimately depend on the regulated movement of chemicals across the plasma membrane. Although recent studies have described some of the genes involved in these transport processes, it is clear that many other essential gene products remain to be identified and characterized. Using a comparative approach, we recently cloned and functionally characterized a new type of organic solute and steroid transporter (OST) from skate, mouse, and human genomes. This transporter is generated by co-expression of two unique gene products, organic solute transporter-alpha and -beta (OSTalpha, OSTbeta). In contrast with most other transporters that are members of gene families, OSTalpha and OSTbeta do not have homologues in the mouse or human genomes. Moreover, these genes are evolutionary conserved and are able to functionally complement each other across species. Preliminary characterization of the transport function and cellular localization of the proteins suggests that OSTalpha-OSTbeta is a critical regulator of the reabsorption of bile acids and other steroids in the intestine, kidney, and other epithelial tissues. Transported substrates include estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, taurocholate, digoxin, and prostaglandin E2, indicating a role in the disposition of key cellular metabolites or signaling molecules. These preliminary studies are consistent with the hypothesis that OSTalpha-OSTbetaa is a heteromeric transporter that is localized to the basolateral membrane of key epithelial tissues, and serves to regulate the disposition of steroid-derived molecules. To test this hypothesis the proposed studies aim to: (1) Define the tissue expression, and cellular and sub-cellular distribution of OSTalpha and OSTbeta, (2) Generate and functionally characterize Osta knockout mice, (3) Examine whether OSTalpha and OSTbeta are forming heterodimers or heteromultimers, and (4) Identify the regions of the OSTalpha and OSTbeta proteins that are critical for plasma membrane delivery and/or functional expression of transport activity. Overall, these studies should provide fundamental information on the mechanisms by which this novel transporter regulates bile acid and steroid homeostasis in mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067214-03
Application #
7216210
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
May, Michael K
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$287,917
Indirect Cost
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Christian, Whitney V; Hinkle, Patricia M (2017) Global functions of extracellular, transmembrane and cytoplasmic domains of organic solute transporter ?-subunit. Biochem J 474:1981-1992
Malik, Sundeep; Dolan, Terrance M; Maben, Zachary J et al. (2015) Adrenocorticotropic Hormone (ACTH) Responses Require Actions of the Melanocortin-2 Receptor Accessory Protein on the Extracellular Surface of the Plasma Membrane. J Biol Chem 290:27972-85
Wheeler, Sadie G; Hammond, Christine L; Jornayvaz, Fran├žois R et al. (2014) Ost?-/- mice exhibit altered expression of intestinal lipid absorption genes, resistance to age-related weight gain, and modestly improved insulin sensitivity. Am J Physiol Gastrointest Liver Physiol 306:G425-38
Ballatori, Nazzareno; Christian, Whitney V; Wheeler, Sadie G et al. (2013) The heteromeric organic solute transporter, OST?-OST?/SLC51: a transporter for steroid-derived molecules. Mol Aspects Med 34:683-92
Christian, Whitney V; Li, Na; Hinkle, Patricia M et al. (2012) ?-Subunit of the Ost?-Ost? organic solute transporter is required not only for heterodimerization and trafficking but also for function. J Biol Chem 287:21233-43
Madejczyk, Michael S; Ballatori, Nazzareno (2012) The iron transporter ferroportin can also function as a manganese exporter. Biochim Biophys Acta 1818:651-7
Ballatori, Nazzareno (2011) Pleiotropic functions of the organic solute transporter Ost?-Ost?. Dig Dis 29:13-7
Soroka, Carol J; Velazquez, Heino; Mennone, Albert et al. (2011) Ost? depletion protects liver from oral bile acid load. Am J Physiol Gastrointest Liver Physiol 301:G574-9
Krance, Suzanne M; Keng, Peter C; Palis, James et al. (2010) Transient glutathione depletion determines terminal differentiation in HL-60 cells. Oxid Med Cell Longev 3:53-60
Soroka, Carol J; Mennone, Albert; Hagey, Lee R et al. (2010) Mouse organic solute transporter alpha deficiency enhances renal excretion of bile acids and attenuates cholestasis. Hepatology 51:181-90

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