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Renal Transport of Organic Anions and Cations

Ryan M. Pelis, Stephen H. Wright

10.1002/cphy.c100084

Source: Volume 1, Issue 4, October 2011

Published online: October 2011

Full Article on Wiley Online Library



Abstract

Organic anions and cations (OAs and OCs, respectively) comprise an extraordinarily diverse array of compounds of physiological, pharmacological, and toxicological importance. The kidney, primarily the renal proximal tubule, plays a critical role in regulating the plasma concentrations of these organic electrolytes and in clearing the body of potentially toxic xenobiotics agents, a process that involves active, transepithelial secretion. This transepithelial transport involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. Basolateral and luminal OA and OC transport reflects the concerted activity of a suite of separate proteins arranged in parallel in each pole of proximal tubule cells. The cloning of multiple members of several distinct transport families, the subsequent characterization of their activity, and their subcellular localization within distinct regions of the kidney, now allows the development of models describing the molecular basis of the renal secretion of OAs and OCs. New information on naturally occurring genetic variation of many of these processes provides insight into the basis of observed variability of drug efficacy and unwanted drug‐drug interactions in human populations. The present review examines recent work on these issues. © 2011 American Physiological Society. Compr Physiol 1:1795‐1835, 2011.

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Figure 1. Figure 1.

Schematic model of the transport processes involved in secretion of organic anions (OAs) by renal proximal tubule cells. The direction of the arrows indicates the direction of net substrate transport. The uptake of OAs across the basolateral membrane by organic anion transporter 1 and 3 (OAT1 and OAT3) occurs via a tertiary active mechanism where (i) Na+,K+‐ATPase creates the sodium gradient that (ii) drives Na+‐dependent αKG2− (Kreb's cycle intermediate) uptake by Na+‐dicarboxylate cotransporter 1 (NaDC1) and NaDC3, and in turn, (iii) the outwardly directed αKG2− gradient energizes OA uptake by OAT1 and OAT3. Although organic anion transporter 2 is suspected of mediating OA uptake, the intracellular counteranion involved in the exchange process has not been clearly established. Na+‐phosphate cotransporter 1 and 4 (NPT1 and NPT4) operate via electrogenic facilitated diffusion, and multidrug resistance‐associated proteins 2 and 4 are ATPases. URAT1 is most noted for its involvement in urate reabsorption via exchange with intracellular monocarboxylates (MC−). The outwardly directed monocarboxylate gradient is maintained by Na+‐dependent monocarboxylate transporters 1 and 2 (SMCT1 and 2). The energetic mechanism of organic anion transporter 4 and 10 (OAT4 and OAT10) has not been clearly established, and thus, it is not clear if they would predominate in OA secretion or reabsorption. However, OA transport by OAT4 is trans‐stimulated by αKG2− and OAT10 by monocarboxylates; the outwardly directed mono‐ and di‐carboxylate gradients may drive OA reabsorption by these transporters, as depicted in the figure.
Figure 2. Figure 2.

Schematic model of the transport processes involved in the secretion or reabsorption of urate by renal proximal tubule (RPT) cells. The direction of the arrows indicates the direction of net substrate transport. Secretion: Urate uptake across the basolateral membrane of RPT cells by organic anion transporter 1 and 3 is driven by the outwardly directed αKG2− gradient, which is maintained by Na+‐dicarboxylate cotransporter 1 (NaDC1) and NaDC3. Although organic anion transporter 2 is suspected of mediating urate uptake, the intracellular counteranion involved in the exchange process has not been clearly established. Na+‐phosphate cotransporter 1 (NPT1), NPT4, and glucose transporter 9 (GLUT9) operate via electrogenic facilitated diffusion, whereas multidrug resistance‐associated proteins 4 is an ATPase. Reabsorption: URAT1 is an exchanger suspected of playing a major role in the uptake of urate across the luminal membrane of RPT cells. The outwardly directed monocarboxylate (MC−) gradient, maintained by the Na+‐dependent monocarboxylate transporters 1 and 2 (SMCT1 and 2), is suspected of providing the energetic basis for urate uptake by urate transporter 1. The energetic mechanism of organic anion transporter 4 and 10 (OAT4 and OAT10) has not been clearly established, and thus, it is not clear if they would predominate in urate secretion or reabsorption. However, OA transport by OAT4 is trans‐stimulated by αKG2− and OAT10 by monocarboxylates; the outwardly directed mono‐ and di‐carboxylate gradients may drive urate reabsorption by these transporters, as depicted in the figure. GLUT9 operates via electrogenic facilitated diffusion, and is suspected of mediating urate efflux across the basolateral membrane.
Figure 3. Figure 3.

(A) Uptake of [3H]ochratoxin A (OTA) by rabbit organic anion transporter 1 (rbOAT1) and rabbit organic anion transporter 3 (rbOAT3) stably expressed in Chinese hamster ovary cells. OTA uptake was expressed as a percentage of the uptake into Chinese hamster ovary cells not expressing the respective transporters (Control). OTA uptake was conducted in the absence or presence of the OAT1 inhibitor para‐aminohippurate (PAH; 2.5 mM) or the OAT3 inhibitor estrone‐3‐sulfate (ES; 1 mM). (B) Effect of PAH and ES either alone or in combination on OTA uptake into freshly isolated rabbit renal proximal tubules in suspension. For comparison, OTA uptake was also conducted in the presence of the dual OAT1 and OAT3 inhibitor, probenecid (Prob).

Modified from 468.
Figure 4. Figure 4.

Shown are two views of a three‐dimensional homology model of human organic anion transporter 1 structure. The model was built using the crystal structure of GlpT (bacterial glycerol‐3‐phosphate/Pi exchanger) as a template 287. (A) View of the model from the cytoplasmic face. (B) Side view of the homology model, with transmembrane spanning helices 2 and 4 omitted to highlight key residues involved in substrate binding. Key residues in substrate binding (orange = Y230; yellow = K431, purple = F438, and red = R466) are exposed to the hydrophilic cleft that is presumed to comprise the translocation pathway in these proteins.
Figure 5. Figure 5.

Model of the regulatory cascade involved in the acute stimulation of OA secretion, presumably through increased expression of organic anion transporter 1 and 3 (OAT1 and OAT3) at the basolateral membranes of renal proximal tubule cells. The arrows indicate the sequence of events beginning with epidermal growth factor (EGF) or insulin binding to their receptors. MEK = mitogen‐activated/extracellular signal‐regulated kinase; ERK1/2 = extracellular signal‐regulated kinase isoforms 1 and 2; PLA2 = phospholipase A2; AA = arachidonic acid; COX1 = cyclooxygenase 1; PGE2 = prostaglandin E2; AC = adenylate cyclase. The dashed arrow indicates trafficking of OAT1 and OAT3 to the basolateral membrane.
Figure 6. Figure 6.

Topology of short and long multidrug resistance‐associated proteins (MRP). All MRPs consist of the core functional unit, multispanning domains (MSD) 1 and 2, Walker A and Walker B motifs, and intracellular nucleotide‐binding domains (NBD) 1 and 2. Long MRPs, such as MRP2, contain a third MSD (MSD0) that is linked to the core functional unit by a cytoplasmic loop (CL3). Topologies predicted by different computer‐assisted algorithms differ, with some favoring MSD comprising four versus six transmembrane spanning helices.

Modified from 94.
Figure 7. Figure 7.

Dependence of substrate concentration on cGMP uptake by multidrug resistance‐associated proteins 4 and estradiol 17β‐D‐glucuronide (E217βG) uptake by multidrug resistance‐associated proteins 2 into membrane vesicles prepared from Sf9 cells that heterologously expressed the transport proteins. In both cases, substrate uptake was sigmoidal with concentration, indicating positive cooperativity.

Data were adapted from 460 and 417.
Figure 8. Figure 8.

Schematic model of the transport processes associated with the secretion of organic cations (OCs) by renal proximal tubule cells. Circles indicate carrier‐mediated transport processes. Arrows indicate the direction of net substrate transport that occurs under physiological conditions. Solid lines depict what are believed to be principal pathways of substrate transport; dotted lines indicate pathways that are believed to be of secondary importance; the dashed line indicates diffusive movement. Following is a brief description of each of the numbered processes currently believed to play a role, direct or indirect, in transepithelial OC secretion. Principal basolateral processes include (i) Na,K‐ATPase; maintains the inwardly directed Na+ gradient and the K+ gradient associated with the inside‐negative membrane potential, both of which represent driving forces associated with active OC secretion. (ii) OCT1, OCT2, and OCT3; support electrogenic uniport (facilitated diffusion) from the blood of type I OCs (these processes are also believed to support electroneutral OC/OC exchange). Note: basolateral OCT expression (both amount and location) is species dependent; for example, in the human it appears that expression of OCT1 is restricted to the luminal membrane (see text). (iii) Diffusive flux of type II OCs. Principal apical transport processes include: (i) MDR1; supports the ATP‐dependent, active luminal export of type II OCs. (ii) NHE3 and NHE8; support the Na+/H+ exchange activity that sustains the inwardly directed electrochemical gradient for H+ that, in turn, supports activity of multidrug and toxin extrusion (MATE) transporters. (iii) MATE1 and MATE2‐K, support the mediated electroneutral exchange of luminal H+ for intracellular type I OCs. (iv) OCT1 (in human kidney); suspected to support reabsorption of selected OCs; (v) OCTN1 and OCTN2; support electrogenic Na‐dependent reabsorptive fluxes of ergothioneine and carnitine, respectively (secondary, postulated, role in the reabsorptive flux of selected OCs). (vi) CTL1?; postulated to support electrogenic choline reabsorption.
Figure 9. Figure 9.

Influence of MATE1 on the renal handling of metformin. (A) Plasma concentration profile of metformin in Mate1 (+/+) (○) and Mate1 (−/−) (•) mice. Metformin and mannitol were administered as a bolus via the jugular vein *w/1% mannitol administered to maintain a sufficient and constant urine flow. Blood samples were collected at the time points indicated. Each point represents the mean ± S.D. for six mice of each genotype. *P <0.05; ***P <0.001, significantly different from Mate1 (+/+) mice. (B) Urinary excretion of metformin in Mate1 (+/+) (open column) and Mate1 (−/−) (closed column) mice. Urine was collected for 60 min after the drug administration. Each column represents the mean ± S.D. for six mice. ***P <0.001, significantly different from Mate1 (+/+) mice. (C) Tissue distribution (a, b) and tissue clearance (c, d) of metformin in Mate1 (+/+) (□) and Mate1 (−/−) (▪) mice.

Tissue concentrations of metformin were determined 60 min after the drug administration. Each column represents the mean ± S.D. for six mice. **P <0.01; ***P <0.001, significantly different from Mate1 (+/+) mice.

[Modified, with permission, from 397, in which experimental details are outlined.]
Figure 10. Figure 10.

Mean plasma concentration‐time profiles for procainamide (□○) and N‐acetylprocainamide (▪•) when given alone (▪□) and when co‐administered orally with 150 mg ranitidine (•○) in six subjects.

[Modified from 356.]
Figure 11. Figure 11.

rOCT2‐mediated inward current and current under conditions of organic cation (OC) exchange in rOCT2‐expressing Xenopus oocytes. (A) The patch pipette (in detached patch mode) was filled with solution containing 20 mM choline, and the bath was superfused with 2 or 20 mM choline, 2 mM tetraethylammonium (TEA), 100 μM quinine, or no substrate, and voltage pulses from −60 to 60 mV were applied after complete solution exchange (indicated by lowercase letters). Under “symmetric” conditions, that is, 20 mM choline in pipette and bath (see a and g), zero net current was observed (indicated by broken line). Complete removal of substrate from the bath lead to an inward‐directed current (downward, see b and e). Superfusion with 2 mM choline (f) lead to a reduced inward current. Addition of 100 μM quinine (c) or 2 mm TEA (h) inhibited the inward current almost completely. (B) An analogous experiment with 2 mM choline in the pipette. The bath was superfused with 1, 2, 5, or 20 mM choline, 100 μM quinine, or no substrate. rOCT2‐mediated currents are seen below (inward directed) and above (outward‐directed) the broken line. Lowercase letters indicate application of voltage pulses.

[Modified, with permission, from 47].
Figure 12. Figure 12.

Charge distribution within the outward‐ and inward‐facing cleft of structure models of rOCT2. (A) Surface representation of rOCT2 with the substrate binding cleft in the outward‐facing (left) and inward‐facing conformation with superimposed contour grid showing isopotential surfaces at (negative, red; positive, blue). (B) Distribution of electrical charges (surface potential map) on the surface of rOCT2 wild‐type and the rOCT2 (E448Q) mutant (site of mutation is indicated by an arrow). In the outward‐facing conformations, negative potentials are shown in red and positive potentials in blue, viewed from the outside. (C) Electrostatic potential mapped onto the surface of rOCT2 wild‐type and rOCT2 (E448Q) mutant (site of mutation is indicated by an arrow) in the inward‐facing conformation; presentation and color coding are as in B. The negative charges within the outward‐facing innermost cavity may “trap” small inorganic cations and translocate them together with the organic cation substrate, whereas the reorientation may be electroneutral (nonselective‐cotransport‐of‐small‐cations hypothesis).

[Modified from 333].
Figure 13. Figure 13.

Structural alignment of 10 most potent OCT2 inhibitors (left) and the pharmacophore model (right), in which the blue sphere represents a positive ion interaction site and the red sphere represents a hydrophobic aromatic interaction site.

[Modified, with permission, from 476].
Figure 14. Figure 14.

Homology models of OCT 3D structure. The model of rOCT1 292 used the crystal structure of LacY (bacterial sugar‐H+ cotransporter) as its template, whereas the model of rbOCT2 469 used the crystal structure of GlpT (bacterial glycerol‐3‐phosphate/Pi exchanger). Both models are viewed from the cytoplasmic aspect of the proteins. In both models, key residues in the binding of substrates (Q448 and D475 in rOCT1 and their OCT2 homologs, E447 and D474, in rbOCT2) are exposed to the hydrophilic cleft between the N‐ and C‐terminal halves that is presumed to comprise the translocation pathway in these proteins.
Figure 15. Figure 15.

(A) hMATE1 model showing side view (top) and the extracellular face (bottom). The principal cleft helices (1, 2, 7, and 8) are labeled in the bottom view. (B) Topological comparison (from the cytoplasmic aspect) of a representative MATE family member (NorM; left) and a representative MFS member (EmrD; right). Below the simplified topology diagram are the x‐ray structures with the TM helices (1‐12 marked).


Figure 1.

Schematic model of the transport processes involved in secretion of organic anions (OAs) by renal proximal tubule cells. The direction of the arrows indicates the direction of net substrate transport. The uptake of OAs across the basolateral membrane by organic anion transporter 1 and 3 (OAT1 and OAT3) occurs via a tertiary active mechanism where (i) Na+,K+‐ATPase creates the sodium gradient that (ii) drives Na+‐dependent αKG2− (Kreb's cycle intermediate) uptake by Na+‐dicarboxylate cotransporter 1 (NaDC1) and NaDC3, and in turn, (iii) the outwardly directed αKG2− gradient energizes OA uptake by OAT1 and OAT3. Although organic anion transporter 2 is suspected of mediating OA uptake, the intracellular counteranion involved in the exchange process has not been clearly established. Na+‐phosphate cotransporter 1 and 4 (NPT1 and NPT4) operate via electrogenic facilitated diffusion, and multidrug resistance‐associated proteins 2 and 4 are ATPases. URAT1 is most noted for its involvement in urate reabsorption via exchange with intracellular monocarboxylates (MC−). The outwardly directed monocarboxylate gradient is maintained by Na+‐dependent monocarboxylate transporters 1 and 2 (SMCT1 and 2). The energetic mechanism of organic anion transporter 4 and 10 (OAT4 and OAT10) has not been clearly established, and thus, it is not clear if they would predominate in OA secretion or reabsorption. However, OA transport by OAT4 is trans‐stimulated by αKG2− and OAT10 by monocarboxylates; the outwardly directed mono‐ and di‐carboxylate gradients may drive OA reabsorption by these transporters, as depicted in the figure.



Figure 2.

Schematic model of the transport processes involved in the secretion or reabsorption of urate by renal proximal tubule (RPT) cells. The direction of the arrows indicates the direction of net substrate transport. Secretion: Urate uptake across the basolateral membrane of RPT cells by organic anion transporter 1 and 3 is driven by the outwardly directed αKG2− gradient, which is maintained by Na+‐dicarboxylate cotransporter 1 (NaDC1) and NaDC3. Although organic anion transporter 2 is suspected of mediating urate uptake, the intracellular counteranion involved in the exchange process has not been clearly established. Na+‐phosphate cotransporter 1 (NPT1), NPT4, and glucose transporter 9 (GLUT9) operate via electrogenic facilitated diffusion, whereas multidrug resistance‐associated proteins 4 is an ATPase. Reabsorption: URAT1 is an exchanger suspected of playing a major role in the uptake of urate across the luminal membrane of RPT cells. The outwardly directed monocarboxylate (MC−) gradient, maintained by the Na+‐dependent monocarboxylate transporters 1 and 2 (SMCT1 and 2), is suspected of providing the energetic basis for urate uptake by urate transporter 1. The energetic mechanism of organic anion transporter 4 and 10 (OAT4 and OAT10) has not been clearly established, and thus, it is not clear if they would predominate in urate secretion or reabsorption. However, OA transport by OAT4 is trans‐stimulated by αKG2− and OAT10 by monocarboxylates; the outwardly directed mono‐ and di‐carboxylate gradients may drive urate reabsorption by these transporters, as depicted in the figure. GLUT9 operates via electrogenic facilitated diffusion, and is suspected of mediating urate efflux across the basolateral membrane.



Figure 3.

(A) Uptake of [3H]ochratoxin A (OTA) by rabbit organic anion transporter 1 (rbOAT1) and rabbit organic anion transporter 3 (rbOAT3) stably expressed in Chinese hamster ovary cells. OTA uptake was expressed as a percentage of the uptake into Chinese hamster ovary cells not expressing the respective transporters (Control). OTA uptake was conducted in the absence or presence of the OAT1 inhibitor para‐aminohippurate (PAH; 2.5 mM) or the OAT3 inhibitor estrone‐3‐sulfate (ES; 1 mM). (B) Effect of PAH and ES either alone or in combination on OTA uptake into freshly isolated rabbit renal proximal tubules in suspension. For comparison, OTA uptake was also conducted in the presence of the dual OAT1 and OAT3 inhibitor, probenecid (Prob).

Modified from 468.


Figure 4.

Shown are two views of a three‐dimensional homology model of human organic anion transporter 1 structure. The model was built using the crystal structure of GlpT (bacterial glycerol‐3‐phosphate/Pi exchanger) as a template 287. (A) View of the model from the cytoplasmic face. (B) Side view of the homology model, with transmembrane spanning helices 2 and 4 omitted to highlight key residues involved in substrate binding. Key residues in substrate binding (orange = Y230; yellow = K431, purple = F438, and red = R466) are exposed to the hydrophilic cleft that is presumed to comprise the translocation pathway in these proteins.



Figure 5.

Model of the regulatory cascade involved in the acute stimulation of OA secretion, presumably through increased expression of organic anion transporter 1 and 3 (OAT1 and OAT3) at the basolateral membranes of renal proximal tubule cells. The arrows indicate the sequence of events beginning with epidermal growth factor (EGF) or insulin binding to their receptors. MEK = mitogen‐activated/extracellular signal‐regulated kinase; ERK1/2 = extracellular signal‐regulated kinase isoforms 1 and 2; PLA2 = phospholipase A2; AA = arachidonic acid; COX1 = cyclooxygenase 1; PGE2 = prostaglandin E2; AC = adenylate cyclase. The dashed arrow indicates trafficking of OAT1 and OAT3 to the basolateral membrane.



Figure 6.

Topology of short and long multidrug resistance‐associated proteins (MRP). All MRPs consist of the core functional unit, multispanning domains (MSD) 1 and 2, Walker A and Walker B motifs, and intracellular nucleotide‐binding domains (NBD) 1 and 2. Long MRPs, such as MRP2, contain a third MSD (MSD0) that is linked to the core functional unit by a cytoplasmic loop (CL3). Topologies predicted by different computer‐assisted algorithms differ, with some favoring MSD comprising four versus six transmembrane spanning helices.

Modified from 94.


Figure 7.

Dependence of substrate concentration on cGMP uptake by multidrug resistance‐associated proteins 4 and estradiol 17β‐D‐glucuronide (E217βG) uptake by multidrug resistance‐associated proteins 2 into membrane vesicles prepared from Sf9 cells that heterologously expressed the transport proteins. In both cases, substrate uptake was sigmoidal with concentration, indicating positive cooperativity.

Data were adapted from 460 and 417.


Figure 8.

Schematic model of the transport processes associated with the secretion of organic cations (OCs) by renal proximal tubule cells. Circles indicate carrier‐mediated transport processes. Arrows indicate the direction of net substrate transport that occurs under physiological conditions. Solid lines depict what are believed to be principal pathways of substrate transport; dotted lines indicate pathways that are believed to be of secondary importance; the dashed line indicates diffusive movement. Following is a brief description of each of the numbered processes currently believed to play a role, direct or indirect, in transepithelial OC secretion. Principal basolateral processes include (i) Na,K‐ATPase; maintains the inwardly directed Na+ gradient and the K+ gradient associated with the inside‐negative membrane potential, both of which represent driving forces associated with active OC secretion. (ii) OCT1, OCT2, and OCT3; support electrogenic uniport (facilitated diffusion) from the blood of type I OCs (these processes are also believed to support electroneutral OC/OC exchange). Note: basolateral OCT expression (both amount and location) is species dependent; for example, in the human it appears that expression of OCT1 is restricted to the luminal membrane (see text). (iii) Diffusive flux of type II OCs. Principal apical transport processes include: (i) MDR1; supports the ATP‐dependent, active luminal export of type II OCs. (ii) NHE3 and NHE8; support the Na+/H+ exchange activity that sustains the inwardly directed electrochemical gradient for H+ that, in turn, supports activity of multidrug and toxin extrusion (MATE) transporters. (iii) MATE1 and MATE2‐K, support the mediated electroneutral exchange of luminal H+ for intracellular type I OCs. (iv) OCT1 (in human kidney); suspected to support reabsorption of selected OCs; (v) OCTN1 and OCTN2; support electrogenic Na‐dependent reabsorptive fluxes of ergothioneine and carnitine, respectively (secondary, postulated, role in the reabsorptive flux of selected OCs). (vi) CTL1?; postulated to support electrogenic choline reabsorption.



Figure 9.

Influence of MATE1 on the renal handling of metformin. (A) Plasma concentration profile of metformin in Mate1 (+/+) (○) and Mate1 (−/−) (•) mice. Metformin and mannitol were administered as a bolus via the jugular vein *w/1% mannitol administered to maintain a sufficient and constant urine flow. Blood samples were collected at the time points indicated. Each point represents the mean ± S.D. for six mice of each genotype. *P <0.05; ***P <0.001, significantly different from Mate1 (+/+) mice. (B) Urinary excretion of metformin in Mate1 (+/+) (open column) and Mate1 (−/−) (closed column) mice. Urine was collected for 60 min after the drug administration. Each column represents the mean ± S.D. for six mice. ***P <0.001, significantly different from Mate1 (+/+) mice. (C) Tissue distribution (a, b) and tissue clearance (c, d) of metformin in Mate1 (+/+) (□) and Mate1 (−/−) (▪) mice.

Tissue concentrations of metformin were determined 60 min after the drug administration. Each column represents the mean ± S.D. for six mice. **P <0.01; ***P <0.001, significantly different from Mate1 (+/+) mice.

[Modified, with permission, from 397, in which experimental details are outlined.]


Figure 10.

Mean plasma concentration‐time profiles for procainamide (□○) and N‐acetylprocainamide (▪•) when given alone (▪□) and when co‐administered orally with 150 mg ranitidine (•○) in six subjects.

[Modified from 356.]


Figure 11.

rOCT2‐mediated inward current and current under conditions of organic cation (OC) exchange in rOCT2‐expressing Xenopus oocytes. (A) The patch pipette (in detached patch mode) was filled with solution containing 20 mM choline, and the bath was superfused with 2 or 20 mM choline, 2 mM tetraethylammonium (TEA), 100 μM quinine, or no substrate, and voltage pulses from −60 to 60 mV were applied after complete solution exchange (indicated by lowercase letters). Under “symmetric” conditions, that is, 20 mM choline in pipette and bath (see a and g), zero net current was observed (indicated by broken line). Complete removal of substrate from the bath lead to an inward‐directed current (downward, see b and e). Superfusion with 2 mM choline (f) lead to a reduced inward current. Addition of 100 μM quinine (c) or 2 mm TEA (h) inhibited the inward current almost completely. (B) An analogous experiment with 2 mM choline in the pipette. The bath was superfused with 1, 2, 5, or 20 mM choline, 100 μM quinine, or no substrate. rOCT2‐mediated currents are seen below (inward directed) and above (outward‐directed) the broken line. Lowercase letters indicate application of voltage pulses.

[Modified, with permission, from 47].


Figure 12.

Charge distribution within the outward‐ and inward‐facing cleft of structure models of rOCT2. (A) Surface representation of rOCT2 with the substrate binding cleft in the outward‐facing (left) and inward‐facing conformation with superimposed contour grid showing isopotential surfaces at (negative, red; positive, blue). (B) Distribution of electrical charges (surface potential map) on the surface of rOCT2 wild‐type and the rOCT2 (E448Q) mutant (site of mutation is indicated by an arrow). In the outward‐facing conformations, negative potentials are shown in red and positive potentials in blue, viewed from the outside. (C) Electrostatic potential mapped onto the surface of rOCT2 wild‐type and rOCT2 (E448Q) mutant (site of mutation is indicated by an arrow) in the inward‐facing conformation; presentation and color coding are as in B. The negative charges within the outward‐facing innermost cavity may “trap” small inorganic cations and translocate them together with the organic cation substrate, whereas the reorientation may be electroneutral (nonselective‐cotransport‐of‐small‐cations hypothesis).

[Modified from 333].


Figure 13.

Structural alignment of 10 most potent OCT2 inhibitors (left) and the pharmacophore model (right), in which the blue sphere represents a positive ion interaction site and the red sphere represents a hydrophobic aromatic interaction site.

[Modified, with permission, from 476].


Figure 14.

Homology models of OCT 3D structure. The model of rOCT1 292 used the crystal structure of LacY (bacterial sugar‐H+ cotransporter) as its template, whereas the model of rbOCT2 469 used the crystal structure of GlpT (bacterial glycerol‐3‐phosphate/Pi exchanger). Both models are viewed from the cytoplasmic aspect of the proteins. In both models, key residues in the binding of substrates (Q448 and D475 in rOCT1 and their OCT2 homologs, E447 and D474, in rbOCT2) are exposed to the hydrophilic cleft between the N‐ and C‐terminal halves that is presumed to comprise the translocation pathway in these proteins.



Figure 15.

(A) hMATE1 model showing side view (top) and the extracellular face (bottom). The principal cleft helices (1, 2, 7, and 8) are labeled in the bottom view. (B) Topological comparison (from the cytoplasmic aspect) of a representative MATE family member (NorM; left) and a representative MFS member (EmrD; right). Below the simplified topology diagram are the x‐ray structures with the TM helices (1‐12 marked).

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Article Title: Renal Transport of Organic Anions and Cations
 

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Ryan M. Pelis, Stephen H. Wright. Renal Transport of Organic Anions and Cations. Compr Physiol 2011, 1: 1795-1835. doi: 10.1002/cphy.c100084