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Mechanism of Iodide/Chloride Exchange by Pendrin

Division of Regenerative Medicine and Therapeutics (A.Y., I.H., N.S., Y.Y., J.M., O.I., C.S.), Department of Genetics and Regenerative Medicine, Tottori University Graduate School of Medicine, and First Department of Internal Medicine (A.Y., S.T., Y.Y., J.M., H.F., H.S., T.Oka., T.Oku., O.I., C.S.), Tottori University Faculty of Medicine, Yonago, Tottori 683-8504, Japan; Genome Technology Branch (E.D.G.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Ohio University School of Osteopathic Medicine and Edison Biotechnology Institute (L.D.K.), Athens, Ohio 45701; and Department of Microbiology (K.S.), Leprosy Research Center, National Institute of Infectious Diseases, Tokyo 189-0002, Japan

Address all correspondence and requests for reprints to: Dr. Akio Yoshida, First Department of Internal Medicine, Tottori University Faculty of Medicine, 36-1 Nishimachi, Yonago, Tottori 683-8504, Japan. E-mail: ayoshida{at}bronze.ocn.ne.jp.

	Abstract

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We performed an electrophysiological study to investigate ion transport of pendrin and thereby understand the pathogenesis of Pendred syndrome. Using pendrin-transfected COS-7 cells, we could show that pendrin transports both iodide and chloride measured as voltage-dependent inward and outward membrane currents. Chloride in the culture medium, [Cl^–]_o, was efficiently exchanged with cytoplasmic iodide, [I^–]_i, under physiological concentrations, indicating that pendrin is important for chloride uptake and iodide efflux. Although exchange of iodide in the medium, [I^–]_o, with cytoplasmic chloride, [Cl^–]_i, was observed, a significantly high concentration of iodide (10 mM) was required. In addition, either iodide or chloride was required on both sides of the cell membrane for the anion exchange activity of pendrin, indicating that iodide and chloride activate the exchange activity of pendrin while they are transported. The present study further supports that pendrin is responsible for the iodide efflux in thyroid cells where intracellular iodide concentration is high and that the general function of pendrin in other tissues is to transport chloride through exchange with other anions.

	Introduction

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PENDRED SYNDROME IS a genetic disorder associated with profound sensorineural hearing loss and thyroid goiter (1, 2, 3, 4). It is one of the most common forms of syndromic deafness; affected individuals typically have structural anomalies of the inner ear (5, 6, 7). Pendred syndrome is also characterized by an impaired organification of iodide in the thyroid, accompanied by goiter and a positive perchlorate discharge test (3, 4).

In 1997, the Pendred syndrome gene (PDS) was identified by a positional cloning strategy (8). The approximately 5-kb PDS transcript showed striking tissue-specific expression, being highly expressed in the thyroid, kidney, and inner ear (8, 9). The gene consists of 21 coding exons and encodes a putative 780-amino-acid protein (pendrin) with 11 or 12 transmembrane domains (8, 10).

Pendrin shows high homology to known sulfate transporters (8); however, using two different expression systems, Xenopus laevis oocytes and Sf9 insect cells, it was demonstrated that pendrin transports iodide and chloride in a competitive manner (11). We have demonstrated that pendrin is important for iodide efflux from thyroid cells and that transport of iodide and chloride is not competitive in mammalian cells (12). Recently it has been demonstrated using polarized mammalian cells that pendrin mediates apical iodide efflux (13). Therefore, it is presumed that the loss of iodide transport across the apical membrane to the colloid lumen of the thyroid, which is the main place of iodide organification, leads to the functional abnormalities of the thyroid in Pendred syndrome. Activities such as chloride/formate and Cl^–/OH^–/HCO₃^– exchanger of pendrin have also been demonstrated using X. laevis oocytes and an HEK-293 expression system (14, 15). Royaux et al. (10) reported that pendrin is expressed on the apical region of intercalated cells of the renal collecting duct and mediates bicarbonate secretion.

Despite the fact that pendrin is important for the transport of chloride, iodide, bicarbonate, and formate in the thyroid, kidney, and inner ear, the electrophysiological mechanism of anion transport by pendrin has not been reported (14, 15). Therefore, we performed an electrophysiological study using pendrin-transfected COS-7 cells. Using this system, we can evaluate ion transport, which can be directly measured as a change of membrane currents by simply changing the concentrations of the ions both inside and outside of the cells. We used iodide and chloride as the anions because it is easy to measure the transport of these anions electrophysiologically. Secretion of fluid into the thyroid follicular lumen, which determines in part the follicular volume of the thyroid, appears to be mediated by Cl^– transport (16, 17, 18). Therefore, at the apical membrane where pendrin is expressed, the Cl^– transport activity of pendrin might also be important in addition to I^– secretion into the follicular lumen.

In the present study, we demonstrated the mechanism of anion transport by pendrin. We show that the function of pendrin is the exchange of chloride with iodide at a physiological concentration.

	Materials and Methods

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Cells
COS-7 cells were maintained in DMEM containing 10% fetal bovine serum (Life Technologies, Inc., Chagrin Falls, OH), 2 mmol/liter L-glutamine, and 1% penicillin and streptomycin. Cell cultures were kept at 37 C in a 5% CO₂ incubator. COS-7 cells grown on plastic slips (Cell disc; Sumitomo Bakelite Co. Ltd., Tokyo, Japan) were cotransfected with an expression vector containing PDS cDNA (10) and pEGFP (Invitrogen Corp., Carlsbad, CA). Transfected cells were visualized by enhanced green fluorescent protein (EGFP) fluorescence and subjected to whole-cell voltage clamp experiments (Fig. 1).

View larger version (81K): [in this window] [in a new window]   FIG. 1. COS-7 cells transiently transfected with pendrin and EGFP genes. A and B, Phase-contrast image (A) and EGFP fluorescence (B) of COS-7 cells 48 h after transfection. COS-7 cells grown on plastic slips were cotransfected with an expression vector containing cDNA for PDS and EGFP. Transfected cells were visualized by EGFP fluorescence and subjected to whole-cell voltage-clamp experiments.

The glass suction pipette was 2 µm in diameter at the tip, and the resistance was 3–5 M when filled with the internal solution. The series resistance was less than 8 M, as examined from the time course of the capacitive current recorded at the start of the whole-cell voltage clamp. The pipette was filled with an internal solution consisting of 140 mM potassium aspartate, 5 mM MgCl₂, 5 mM EGTA, 5 mM K₂ATP and 5 mM HEPES (pH 7.3). To change the concentration of potassium, chloride, and iodide, KCl was replaced with TEA-Cl, potassium aspartate, and KI.

We used 0–140 mEq of chloride concentration in the perfusing solution, because the ion current was saturated in this range in our preliminary study. The iodide concentration in the perfusing solution was 0–10 mM, because our previous study revealed that iodide uptake by pendrin was observed where the iodide concentration in the medium was over 1 mM (12). Saturation of ion current was also observed at these iodide concentrations.

Pendrin-transfectded COS-7 cells were patch clamped to measure membrane current produced by chloride and iodide transport. To examine iodide and chloride efflux from the cells, the cytoplasmic solution was replaced with a solution containing various concentrations of chloride and iodide using the pipette for voltage clamp. To examine chloride and iodide uptake, the concentration of these anions in the bath solution was changed by switching the perfusates at the inlet of the recording chamber.

Membrane currents were filtered at 1 kHz and measured using Axopatch 200A and p-clamp 6 (Axon Instruments, Inc., Foster City, CA). For current-voltage (I-V) relation measurements, ramp pulses were used. When the cytoplasmic side of the cell membrane is depolarized up to +100 mV by ramp pulse, chloride and iodide should be transported inwardly. Inward transport of chloride and iodide produce an outward membrane current. When the cytoplasmic side of the cell membrane is hyperpolarized up to –160 mV, chloride and iodide should be transported outwardly. Outward transport of chloride and iodide produce a voltage-dependent inward membrane current.

Statistical analysis
Values are the mean ± SD of five experiments where noted. The significance of experimental values was determined by ANOVA in which P < 0.05 was considered to be significant. To calculate the ion concentration that gives half the value of the membrane current at the saturating external ion concentration (K_0.5), outward and inward currents measured at +80 mV and at –150 mV were analyzed with the OriginR 7.0 program (OriginLab Co., Northampton, MA).

	Results

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In this study, we used COS-7 cells transiently transfected with pendrin to examine the electrophysiological characteristics of pendrin. In this transient expression system, more than 40% of the cells were EGFP positive and readily used in the patch-clamp experiment (Fig. 1). We chose cells showing almost the same level of EGFP expression for the electrophysiological study. Cl^– and I^– in the cytoplasm are expressed as [Cl^–]_o and [I^–]_o, respectively, and Cl^– and I^– in the medium are expressed as [Cl^–]_i and [I^–]_i, respectively, in the following text.

Chloride current in control and pendrin-transfected COS-7 cells
Control COS-7 cells and pendrin-transfected COS-7 cells were voltage clamped using a pipette filled with internal solution containing 10 mM Cl^– and perfused with Tyrode’s solution containing 140 mM NaCl or chloride-free perfusing solution. As shown in Fig. 2, the membrane current in control cells was very small and was not affected by chloride. On the other hand, significant inward and outward currents were observed in pendrin-transfected cells. To study whether this current represented chloride transport by pendrin or not, we examined the chloride dependency of this membrane current.

View larger version (18K): [in this window] [in a new window]   FIG. 2. Chloride current in control and pendrin-transfected COS-7 cells. Control cells and pendrin-transfected COS-7 cells were patch clamped with a pipette filled with internal solution containing 10 mM Cl– and perfused with a solution containing 0 or 140 mM Cl–; then membrane currents induced by ramp pulses were measured. This figure shows a representative result from five independent experiments. The membrane current was very small and was not chloride dependent in control cells. On the other hand, a significant current was observed in pendrin-transfected cells.

Figure 3 shows the I-V relation curve of membrane current measured using ramp pulses. Outward and inward membrane currents decreased as the concentration of Cl^– in the perfusing solution decreased. Outward membrane current represents influx, whereas an inward membrane current represents efflux of chloride.

View larger version (16K): [in this window] [in a new window]   FIG. 3. Membrane currents in pendrin-transfected COS-7 cells under a physiological concentration of cytoplasmic chloride and various concentrations of chloride in the perfusing solution. Pendrin-transfected COS-7 cells were patch clamped with a pipette filled with internal solution containing 10 mM Cl– and perfused with 0–140 mM chloride. I-V relations of membrane current for each chloride concentration were measured using ramp pulses. The representative results from five independent experiments are shown. The ordinate represents the membrane current and the abscissa the membrane potential.

Influx of iodide and efflux of chloride in pendrin-transfected COS-7 cells
To examine the influx of iodide and efflux of chloride through pendrin, control and pendrin-transfected COS-7 cells were patch clamped with the pipette filled with an internal solution containing 10 mM Cl^– and perfused with a chloride-free solution containing 0–10 mM iodide; the I-V relation was then determined using ramp pulses. As shown in Fig. 4, both inward and outward currents were observed in pendrin-transfected COS-7 cells. No iodide-dependent current was observed in control cells (data not shown).

View larger version (16K): [in this window] [in a new window]   FIG. 4. Membrane currents in pendrin-transfected COS-7 cells under a physiological concentration of cytoplasmic chloride and various concentrations of iodide in the perfusing solution. Pendrin-transfected COS-7 cells were patch clamped with a pipette filled with internal solution containing 10 mM Cl– and perfused with 0–10 mM iodide. I-V relations of membrane current for each iodide concentration were measured using ramp pulses. Representative results from five independent experiments are shown. The ordinate represents the membrane current and the abscissa the membrane potential.

Efflux of iodide at physiological cytoplasmic concentrations of iodide
We have reported that thyroid cells are able to concentrate iodide at least up to 2 mM (12). So, we used 0.5–10 mM iodide in the cytoplasm to examine whether at physiological cytoplasmic concentrations iodide is transported by pendrin.

Control COS-7 cells and pendrin-transfected COS-7 cells were patch clamped using a pipette filled with 0.5–10 mM KI and perfused with a solution containing 0–140 mM chloride, and the I-V relation was determined using ramp pulses (Fig. 5, A–C). Under these conditions, inward current indicates the efflux of iodide and outward current indicates the influx of chloride. The membrane current was very small and was not affected by chloride in control cells. On the other hand, iodide efflux was detected even at 0.5 mM iodide, indicating that iodide efflux mediated by pendrin occurs under physiological concentrations of cytoplasmic iodide. Similar to the transport of chloride under conditions of [Cl^–]_o/[Cl^–]_i, a dose- and membrane potential-dependent chloride influx was observed. Also, iodide efflux measured as the inward current depended on the concentration of chloride in the perfusing solution, and the current reflecting iodide efflux was very small when the chloride was removed from perfusing solution, indicating that chloride is also an activator of iodide efflux.

View larger version (27K): [in this window] [in a new window]   FIG. 5. Membrane currents in pendrin-transfected cells under physiological concentrations of cytoplasmic iodide and various concentrations of chloride in the perfusing solution. Pendrin-transfected COS-7 cells were patch clamped with a pipette filled with an internal solution containing 0.5 (A), 1 (B), and 10 (C) mM I– and perfused with 0–140 mM chloride. I-V relations of membrane current for each chloride concentration were measured using ramp pulses. Representative results from five independent experiments are shown. The ordinate represents the membrane current and the abscissa the membrane potential.

Pendrin-transfected COS-7 cells were patch clamped with a pipette filled with potassium aspartate. Then, cells were perfused with a solution containing 140 mM Cl^– or 10 mM I^–, and the I-V relation of membrane current was determined using ramp pulses (Fig. 6). Under these conditions, it was expected that the inward current, which represents the efflux of anions would not be observed and that the outward current produced by the influx of chloride or iodide would not be decreased. The inward current was not observed as expected; however, the outward current was not observed either. Although only chloride influx is shown in Fig. 6, the same result was obtained for iodide influx (data not shown). These observations indicate that the presence of chloride or iodide on both sides of the membrane is required for chloride or iodide transport by pendrin.

View larger version (12K): [in this window] [in a new window]   FIG. 6. Membrane current in pendrin-transfected cells without Cl– or I– in the cytoplasmic solution. Pendrin-transfected cells were patch clamped with a pipette filled with potassium aspartate and perfused with 140 mM sodium gluconate, 140 mM chloride, and 10 mM iodide. The I-V relation of membrane current was measured using ramp pulses. Representative results from five independent experiments are shown. The ordinate represents the membrane current and the abscissa the membrane potential.

View larger version (24K): [in this window] [in a new window]   FIG. 7. Difference of K0.5 for chloride (external chloride concentration that gives half the value of membrane current at a saturating external chloride concentration) in [Cl–]o/[I–]i and [Cl–]o/[Cl–]i exchange. The cytoplasmic solution was replaced with a solution that contained 10 (A), 1 (B), or 0.5 (C) mM iodide or 10 mM chloride (D); then membrane currents were measured as [Cl–]o was changed from 0–140 mM. The abscissa represents the membrane current and the ordinate [Cl–]o. To calculate the chloride concentration that gives half the value of the membrane current at the saturating external chloride concentration (K0.5), the value of the outward current and that of the inward current measured at +80 mV () and –150 mV () for each [Cl–]o concentration were analyzed.

[I^–]_o/[Cl^–]_i exchange is more efficient than [Cl^–]_o/[Cl^–]_i exchange
We then examined K_0.5 for iodide (external iodide concentration that gives half the value of membrane current at a saturating external iodide concentration) in [I^–]_o/[Cl^–]_i exchange. The pipette was filled with a solution that contained 10 mM chloride, and then membrane currents were measured as [I^–]_o was changed from 0–20 mM. The values of the outward and inward current measured at +80 mV and at –150 mV for each [I^–]_o concentration were analyzed (Fig. 8). The K_0.5 for iodide was 7.02 ± 1.85 mM. This value for [I^–]_o/[Cl^–]_i exchange was significantly lower than that of [Cl^–]_o/[Cl^–]_i exchange. This fact indicates that [I^–]_o/[Cl^–]_i exchange is also carried out more efficiently than [Cl^–]_o/[Cl^–]_i exchange.

View larger version (17K): [in this window] [in a new window]   FIG. 8. K0.5 for iodide (external iodide concentration that gives half the value of membrane current at a saturating external iodide concentration) in [I–]o/[Cl–]i exchange. The cytoplasmic solution was replaced with a solution that contained 10 mM chloride; then membrane currents were measured as [I–]o was changed from 0–20 mM. To calculate the iodide concentration that gives half the value of the membrane current at the saturating external iodide concentration (K0.5), the value of the outward current and that of the inward current measured at +80 mV () and –150 mV () for each [I–]o concentration were analyzed.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
In the present report, we investigated ion transport by pendrin electrophysiologically. Pendrin has been reported to be important for anion transport and to function as an anion exchanger; however, the precise mechanism of anion transport has not been clear.

Large inward and outward currents were observed when pendrin-transfected COS-7 cells were voltage clamped with a pipette filled with Cl^– and perfused with a Cl^–-containing solution (Fig. 2). The current depended on the membrane potential and the Cl^– concentration in the perfusing solution. It was considered that this current was produced by the chloride transport. The presence of chloride in both sides of the membrane was required for the influx and efflux of chloride, indicating that chloride is the anion that is transported and, at the same time, an activator of pendrin. This phenomenon was consistent with the results of a previous study in which we used the radiolabeled anions (12). In addition, we have shown that chloride also stimulated iodide efflux by pendrin. In the study by Scott et al. (11), the presence of formate or chloride in the medium was essential for chloride/formate efflux from the cell. A similar phenomenon has been demonstrated in the case of the Na⁺/Ca²⁺ exchanger (22). In ion transport by this exchanger, Ca²⁺ is the ion that is transported and at the same time the activator of the exchanger (22). Although it was not clear whether pendrin is an anion transporter or an exchanger, our study and others indicate that pendrin functions as an anion exchanger (14, 15). Figure 9 summarizes the mechanism of anion transport by pendrin as a schematic representation.

View larger version (16K): [in this window] [in a new window]   FIG. 9. Mechanism of anion exchange. Anion exchange is carried out by pendrin. Under depolarized conditions influx of anion (A–) is larger than the efflux of anion (B–), and an outward current was observed. Under the hyperpolarized conditions the efflux of anion (B–) is larger than the influx of anion (A–) and an inward current was observed.

In the present study, pendrin has been found to function as a Cl^–/Cl^– exchanger, but exchange of the same ion is not considered to be physiologically plausible. We considered that Cl^–/Cl^– exchange was not carried out under physiological conditions because the half-maximum concentration of Cl^– for Cl^–/Cl^– exchange was too high. If pendrin was localized on the basal membrane that faces to the tissue fluid containing 110 mM Cl^–, pendrin would transport Cl^– outwardly by Cl^–/Cl^– exchange activity. However, pendrin has been reported to localize on the apical membrane and face to the follicular colloid of the thyroid or to the tubular fluid in the kidney. These fluids will not contain enough concentrations of chloride to activate Cl^–/Cl^– exchange.

Therefore, we next investigated whether iodide is transported under more physiological conditions or not. We examined the [Cl^–]_o/[I^–]_i exchange because human thyroid expresses pendrin at high levels and is considered as an iodide transporter. Electrophysiological evaluation of iodide transport can be performed more accurately than that of bicarbonate or formate transport. As a result, iodide was exchanged with chloride more efficiently than Cl^–/Cl^– exchange at low concentrations. We have shown that thyroid cells can concentrate up to 2 mM iodide (12); therefore, the 0.5 mM iodide in the cytoplasmic solution used in this study was within the physiological range. As sodium iodide symporter (NIS) is expressed on the basolateral membrane and pendrin is expressed on the apical membrane (10), these findings were consistent with the vectorial transport of iodide from the perivascular space to the thyrocyte and then to the follicular lumen as demonstrated by Gillam et al. (13). NIS accumulates iodide, which results in an increase of the cytosolic iodide concentration. Iodide may then be exchanged with chloride, which is in the follicle in a concentration-dependent and membrane potential-dependent manner by pendrin. In this exchange, a high concentration of Cl^– in the follicular lumen is not required, because the K_0.5 of chloride concentration for [Cl^–]_o/[I^–]_i exchange is low. Thyrocytes express pendrin only on the apical membrane but not on basolateral membrane. Because of this, pendrin can carry [Cl^–]_o/[I^–]_i exchange efficiently at the apical membrane by avoiding Cl^–/Cl^– exchange through the basement membrane that faces perivascular fluid containing 110 mM Cl^–. In this sense, the difference in K_0.5 of Cl^– for [Cl^–]_o/[Cl^–]_i and [Cl^–]_o/[I^–]_i exchange seems to be important. This difference allows pendrin to avoid [Cl^–]_o/[Cl^–]_i exchange and to carry out [Cl^–]_o/[I^–]_i exchange efficiently.

We have previously reported the existence of cAMP-dependent potassium channels on the thyrocyte cell membrane (26). TSH activates this channel and then hyperpolarizes the cell membrane. Because inward transport and outward transport of iodide by NIS and pendrin are carried out more efficiently under hyperpolarized conditions, potassium channels will also be important for iodide transport in the thyroid.

It is considered that defective iodide transport in the thyroid is the major factor that contributes to the development of goiter in patients with Pendred syndrome. However, goiter development and hypothyroidism vary among patients, suggesting that nutritional iodide intake might be another important factor. If iodide intake is low, patients may develop TSH-induced hyperplasia of thyroid cells. In addition to these mechanisms, it will also be possible to presume that the lack of regulation of water distribution might further modulate the phenotype of thyroid disease in patients with Pendred syndrome. It was shown that thyrocytes regulate water distribution by transporting Cl^– (16, 17, 18, 27, 28). Therefore, regulation of water distribution by [Cl^–]_o/[I^–]_i exchange mediated by pendrin might be important for the physiological function of the thyroid. It is well known that a defective chloride absorption in patients with cystic fibrosis transmembrane conductance regulator (CFTR) can be associated with multinodular goiter (18). Changes in water distribution will alter the concentration of thyroglobulin and follicle size.

A similar mechanism of chloride/iodide exchange is predictable in chloride/bicarbonate or chloride/formate exchange by pendrin in the kidney or inner ear. Scott et al. (15) showed using X. laevis oocytes that pendrin is a chloride/formate exchanger, and it was suggested that chloride/formate exchange may be the main function of pendrin in the inner ear. They also suggested that loss of chloride transport may lead to an abnormal salt and water flux accompanied by subsequent dilation of the vestibular aqueduct and a loss of the normal architecture of the cochlea (15).

When 10 mM iodide exists in the medium, chloride, which is in a physiological cytoplasmic concentration, is efficiently exchanged with iodide. Therefore, it may be possible to presume that pendrin is important for chloride secretion from cells and that this occurs through exchange with other ions around the cells.

In conclusion, we have demonstrated that pendrin is an anion exchanger that is important for iodide efflux from thyroid cells and that it is also important for the regulation of chloride and water distribution in other tissues.

	Footnotes

 
Abbreviations: EGFP, Enhanced green fluorescent protein; NIS, sodium iodide symporter; TEA, tetraethylammonium.

Received January 16, 2004.

Accepted for publication May 12, 2004.

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