The ability to transport solutes across epithelial membranes is a vital function of many organs, e.g., kidney. In turn, epithelial transport depends upon individual transport systems located in apical (BBM) and basolateral (BLM) membranes. Because of their complex organization, functional importance, and exposed location, epithelial membranes are particularly susceptible to toxic effects of foreign chemicals. Recent work has focused on the renal organic anion transport system, since this system determines the extent of elimination of toxic xenobiotics. Using p-aminohippuric acid (PAH), a model substrate for this system, it was shown that transport requires the coordinated action of two distinct carrier proteins. One mediates exchange of external PAH for internal glutaric acid (or alpha-ketoglutarate). The second taps energy stored in the Na gradient to drive glutarate back into the cell, maintaining the steep (in greater than out) glutarate gradient needed to drive PAH uptake. Together the two systems indirectly couple BLM PAH transport to the sodium gradient and metabolic energy stores. BBM are unable to couple the two processes. Thus, PAH secretion requires BLM uptake and intracellular accumulation, followed by exit of PAH down its electrochemical gradient at the BBM. Studies using electrophysiological and radiochemical techniques to examine organic cation transport (the second major xenobiotic excretory pathway) show that the basolateral step in secretion of the model organic cation, tetraethylammonium (TEA), is carrier-mediated and strongly potential dependent. To focus on intracellular events, including binding, subcellular compartmentalization, and information transfer between the surface membrane and intracellular organelles, cryomicrodissection and microinjection techniques were developed in amphibian oocytes. Particularly striking was the observation that intracellular insulin, at doses (0.5-5 pmoles) too low to alter surface membrane transport, caused marked changes in both protein and RNA synthesis rates. These preliminary results argue strongly for a physiological role of intracellular insulin receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080031-12
Application #
3941594
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
1987
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Srimaroeng, Chutima; Cecile, Jennifer Perry; Walden, Ramsey et al. (2013) Regulation of renal organic anion transporter 3 (SLC22A8) expression and function by the integrity of lipid raft domains and their associated cytoskeleton. Cell Physiol Biochem 31:565-78
Barros, Scott A; Srimaroeng, Chutima; Perry, Jennifer L et al. (2009) Activation of protein kinase Czeta increases OAT1 (SLC22A6)- and OAT3 (SLC22A8)-mediated transport. J Biol Chem 284:2672-9
Srimaroeng, C; Perry, J L; Pritchard, J B (2008) Physiology, structure, and regulation of the cloned organic anion transporters. Xenobiotica 38:889-935
Bow, Daniel A J; Perry, Jennifer L; Miller, David S et al. (2008) Localization of P-gp (Abcb1) and Mrp2 (Abcc2) in freshly isolated rat hepatocytes. Drug Metab Dispos 36:198-202
Kimura, T; Perry, J; Anzai, N et al. (2007) Development and characterization of immobilized human organic anion transporter-based liquid chromatographic stationary phase: hOAT1 and hOAT2. J Chromatogr B Analyt Technol Biomed Life Sci 859:267-71
Aslamkhan, Amy G; Thompson, Deborah M; Perry, Jennifer L et al. (2006) The flounder organic anion transporter fOat has sequence, function, and substrate specificity similarity to both mammalian Oat1 and Oat3. Am J Physiol Regul Integr Comp Physiol 291:R1773-80
Bow, Daniel A J; Perry, Jennifer L; Simon, John D et al. (2006) The impact of plasma protein binding on the renal transport of organic anions. J Pharmacol Exp Ther 316:349-55
Perry, Jennifer L; Dembla-Rajpal, Neetu; Hall, Laura A et al. (2006) A three-dimensional model of human organic anion transporter 1: aromatic amino acids required for substrate transport. J Biol Chem 281:38071-9
Srimaroeng, Chutima; Chatsudthipong, Varanuj; Aslamkhan, Amy G et al. (2005) Transport of the natural sweetener stevioside and its aglycone steviol by human organic anion transporter (hOAT1; SLC22A6) and hOAT3 (SLC22A8). J Pharmacol Exp Ther 313:621-8
Pritchard, John B; Miller, David S (2005) Expression systems for cloned xenobiotic transporters. Toxicol Appl Pharmacol 204:256-62

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