Download Controversies Concerning the Role of Pendrin as an Apical Iodide

Review
Cellular Physiology
and Biochemistr
Biochemistryy
Cell Physiol Biochem 2011;28:485-490
Accepted: September 28, 2011
Controversies Concerning the Role of Pendrin as
an Apical Iodide Transporter in Thyroid Follicular
Cells
Aigerim Bizhanova and Peter Kopp
Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern
University, Chicago
Abstract
Pendred syndrome is an autosomal recessive
disorder defined by sensorineural deafness, goiter
and a partial organification defect of iodide. It is caused
by biallelic mutations in the multifunctional anion
transporter pendrin/SLC26A4. In human thyroid
tissue, pendrin is localized at the apical membrane of
thyroid follicular cells. The clinical phenotype of
patients with Pendred syndrome and the fact that
pendrin can mediate iodide efflux in transfected cells
suggest that this anion exchanger may be involved
in mediating iodide efflux into the follicular lumen, a
key step in thyroid hormone biosynthesis. This
concept has, however, been questioned. This review
discusses supporting evidence as well as arguments
questioning a role of pendrin in mediating iodide efflux
in thyrocytes.
Copyright © 2011 S. Karger AG, Basel
Introduction
Pendred syndrome (OMIM 274600) is an autosomal
recessive disorder defined by sensorineural deafness,
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goiter, and a partial defect in the organification of iodide
[1, 2]. In 1958, Morgans and Trotter demonstrated that
patients with Pendred syndrome have a partial iodide
organification defect when submitted to a perchlorate
discharge test [3], a finding indicating an inefficient
synthesis of thyroid hormone. The molecular defect of
Pendred syndrome consists in biallelic mutations in the
SLC26A4 (Solute Carrier 26A4) gene, also referred to
as PDS (Pendred Syndrome) gene, which encodes pendrin, a multifunctional anion transporter [4]. Pendrin has
affinity for chloride, iodide, bicarbonate, hydroxide, thiocyanate and formate [5-9]; whether they are all physiological ligands remains unknown. In the thyroid, pendrin
has been implicated in playing a role in mediating efflux
of iodide into the follicular lumen, the functional unit for
the synthesis of thyroid hormones, which are essential
regulators of normal development, growth and metabolism
[10].
Thyroid hormone biosynthesis
The synthesis of thyroid hormones, thyroxine (T4)
and triiodothyronine (T3), requires a normally developed
thyroid gland, an adequate iodide intake and a series of
regulated biochemical steps in thyroid follicular cells,
which form the spherical thyroid follicles [10]. At the
Peter Kopp, MD
485
Director ad interim Center for Genetic Medicine, Division of Endocrinology
Metabolism and Molecular Medicine, Northwestern University
Tarry 15, 303 East Chicago Avenue, Chicago, IL 60611 (USA)
Tel. +1312 503 1394, Fax +1312 908 9032, E-Mail [email protected]
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Key Words
Pendred syndrome • Pendrin • SLC26A4 • Thyroid
hormone synthesis • Goiter • Hypothyroidism
basolateral membrane of thyrocytes, the Na+/K+-ATPase
generates a sodium gradient that permits the sodium-iodide
symporter (NIS) to mediate iodide uptake [11, 12]. Iodide
then translocates to the apical membrane and reaches
the follicular lumen through the apical membrane. While
it has been assumed that iodide moves across the apical
membrane primarily because of the electrochemical
gradient, studies in frozen sections demonstrated that it is
first accumulated in the cytoplasm and only later in the
lumen [13], and apical iodide efflux is rapidly accelerated
in polarized cells after exposure to thyroid stimulating
hormone (TSH) [14]. Electrophysiological studies using
inverted plasma membrane vesicles suggested the
existence of two apical iodide channels [15], but their
molecular identity has not been determined. One of the
channels appears to have a high permeability and
specificity for iodide (Km ~ 70 µM), while the second
channel has a much lower affinity (Km ~ 33 mM). Once
in the follicular lumen, iodide is oxidized by the membranebound enzyme thyroid peroxidase in the presence of
hydrogen peroxide (H2O 2). Oxidized iodide is then
organified into selected tyrosyl residues of thyroglobulin,
a very large secreted glycoprotein that serves as the
scaffold for thyroid hormone synthesis, and this results in
the formation of mono- and diiodotyrosines (MIT, DIT).
In the subsequent coupling reaction, which is also
catalyzed by thyroid peroxidase, two iodotyrosines are
coupled to form either T4 or T3. Iodinated thyroglobulin
is engulfed by thyrocytes through macro- and
micropinocytosis and digested in lysosomes. Released T4
and T3 are secreted into the bloodstream at the basolateral
membrane, at least in part by the recently identified
monocarboxylate transporter MCT8 [16]. In contrast,
MIT and DIT are deiodinated by an intracellular
iodotyrosine dehalogenase (DEHAL1); the released
iodide, a scarce micronutrient, is subsequently recycled
back into the follicular lumen [10, 17].
have a rather mild partial organification defect (PIOD)
[3, 21]. In a study evaluating patients with a standardized
perchlorate test, all patients with biallelic mutations in the
SLC26A4 gene had a partial iodide organification defect,
irrespective of the presence or absence of a goiter [22].
This contrasts with the findings of others [23-25], who
reported that a subset of patients with biallelic mutations
may be bare of any thyroid abnormalities. In the latter
studies, the specific procedure and the threshold chosen
for the perchlorate test have not been reported in detail.
Although patients with Pendred syndrome only have
a PIOD, they occasionally develop hypothyroidism, albeit
only rarely. It is generally thought that the development
of hypothyroidism in patients with Pendred syndrome
occurs under conditions of a low nutritional iodide intake
[26-30]. For example, patients with Pendred syndrome
from an iodide-deficient region from Northern Mexico
have been found to have overt congenital hypothyroidism
[31]. In contrast, in patients with biallelic mutations in the
SLC26A4 gene from countries with a high iodide intake
such as Japan and Korea, there are no reports documenting hypothyroidism in affected individuals [32-34].
Of course, it should be kept in mind that autoimmune
thyroiditis, which is common in the general population,
can also affect individuals with Pendred syndrome [35].
Goiter development is highly variable among patients
with biallelic mutations in the SLC26A4 gene, even among
affected siblings, and in some patients the thyroid is not
enlarged and serum thyroglobulin levels, a marker for
thyroid cell mass, which typically parallels the extent of
the thyroid enlargement, are not elevated [27, 36]. These
findings may, in part, be explained by nutritional iodide
intake, but most likely this phenotypic heterogeneity also
involves the influence of genetic modifiers.
Thyroid phenotype in patients with biallelic
SLC26A4 mutations
The perchlorate test permits to evaluate whether
iodide is organified normally or not [18]. In a normal
individual, less than 10% of radioiodide accumulated in
thyrocytes is not organified into thyroglobulin. In some
patients with congenital hypothyroidism [19], the perchlorate test reveals a total organification defect (TIOD), for
example in patients homozygous for completely inactivating mutations of thyroid peroxidase [20]. This contrasts
with the findings in patients with Pendred syndrome, who
In thyroid follicular cells, pendrin is expressed at the
apical membrane [37]. The apical expression pattern and
pendrin’s ability to transport iodide in Xenopus oocytes
[7], suggested that pendrin is one of the entities mediating
apical iodide efflux [37]. In addition, the PIOD present in
patients with biallelic SLC26A4 mutations is consistent
with a potential role of pendrin in thyroid hormone synthesis.
Functional studies of pendrin in Xenopus oocytes
initially revealed that pendrin mediates uptake of chloride
and iodide in a sodium-independent manner [7]. This was
followed by a series of studies in transfected mammalian
cells. In non-polarized Chinese hamster ovary (CHO) cells
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Bizhanova/Kopp
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Cell Physiol Biochem 2011;28:485-490
Expression and putative function of
pendrin in the thyroid
expressing NIS, which mediates iodide uptake in a
perchlorate-sensitive manner, the presence of pendrin
leads to the efflux of iodide [38]. In time-course experiments measuring iodide release, human embryonic kidney
cells transfected with NIS alone demonstrate a slow,
time-dependent iodide efflux, whereas cells coexpressing
pendrin and NIS exhibit a very rapid efflux of iodide [39].
In polarized Madin-Darby canine kidney (MDCK) cells
cultured on semipermeable membranes in a bicameral
system, cells stably transfected with NIS display a significant increase in intracellular iodide uptake compared to
untransfected MDCK cells [39]. This contrasts with cells
expressing NIS and pendrin, which show significant iodide
transport into the apical chamber, and, hence, a significant
drop in intracellular iodide content. Cells expressing only
pendrin show lower intracellular iodide levels than
untransfected MDCK cells, but higher levels in the apical
chamber; this finding suggests that pendrin facilitates apical
release of iodide after its uptake at the basolateral
membrane, which is presumably mediated by unspecific
chloride channels. Taken together, these observations
suggest that pendrin is able to mediate vectorial iodide
transport at the apical membrane in polarized cells [39].
Electrophysiological studies using transfected COS7 cells also reveal that pendrin mediates iodide efflux,
and the currents demonstrating iodide efflux are higher
with increasing extracellular chloride concentrations [40].
More recent findings in Xenopus oocytes demonstrate clearly that SLC26A4 functions as a coupled,
electroneutral iodide/chloride, iodide/bicarbonate and
chloride/bicarbonate exchanger with a 1:1 stoichiometry
[41]. Of particular importance in this context is the fact
that iodide is the preferred anion and that SLC26A4
transports iodide in the presence of high chloride [41].
This study also demonstrated luminal iodide secretion in
parotis gland ducts, emphasizing that SLC26A4 has a
preferential affinity for iodide [41].
The effects of TSH, the main regulator of thyroid
cell function and growth, on pendrin expression and
function have provided results that are, in part, controversial. In FRTL-5 rat thyroid cells, low doses of TSH do
not induce SLC26A4 mRNA determined by Northern blot
analyses [37]. This contrasts with findings in the same
cell line documenting induction of SLC26A4 mRNA by
RT-PCR after exposure to TSH and forskolin [42], as
well as findings in the PCCL3 rat thyroid cell line reporting
increased expression of pendrin mRNA, determined by
RT-PCR, and protein after exposure to high doses of TSH,
forskolin and 8-Bromo-cAMP [43]. It is well established,
that iodide efflux at the apical membrane is rapidly acce-
lerated by TSH [44-46]. Forskolin-treatment of cells transfected with pendrin results in a rapid increase in membrane insertion and promotes increased iodide efflux [47],
an effect that seems to involve the protein kinase A
pathway based on studies in PCCL3 rat thyroid cells [48],
findings that would be consistent with a role of pendrin in
mediating iodide efflux. Another study reported a delayed
translocation of pendrin from the cytosol to the plasma
membrane after activation of the PKC pathway following
exposure of cultured rat thyroid PCCl3 cells to insulin [43].
Only a small number of the large number of reported
mutations (>170) have been tested functionally in terms
of iodide or halide transport [39, 49-51]. The diseasecausing mutations result in a complete or partial loss of
function in terms of mediating iodide efflux [39, 49, 51,
52], a finding that is also demonstrable in time-course
experiments [39]. Fluorometric methods that allow monitoring the intracellular halide content or the pH have been
used for selected mutants, and also reveal an absent or
partially impaired ability to transport iodide, chloride and
bicarbonate [51-53]. Many of the characterized mutations
are retained in intracellular compartments, most likely the
endoplasmic reticulum [54]. As illustrated in a manuscript
by Dossena et al. in this issue, some of the reported
sequence alterations are functionally irrelevant and simply
reflect polymorphisms in the SLC26A4 gene [55].
Pendrin Function in the Thyroid
Cell Physiol Biochem 2011;28:485-490
Several observations have led to questioning the
concept that pendrin plays a physiological role in mediating
apical iodide transport in thyroid follicular cells [56, 57].
The fact that some individuals with biallelic mutations in
the SLC26A4 gene have no or only a mild thyroidal
phenotype [30], indicates that iodide crosses the apical
membrane independently of pendrin through another iodide
channel or unspecific channels. Thus, the relative importance of pendrin remains uncertain. Knockout mice with
targeted disruption of the Slc26a4 gene faithfully replicate
the phenotype at the level of the inner ear and continue
to provide important insights into the underlying pathophysiology [58-60], but they do not develop a goiter or
abnormal thyroid hormone levels [58], even under conditions of iodine deficiency [61, 62], questioning an important
role of pendrin in iodide metabolism, at least in the mouse.
It has been emphasized that the intracellular affinity
of pendrin for iodide must be substantially higher than for
chloride in order to mediate iodide efflux [56]. Although
exact affinity constants are not available, it has become
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Controversies concerning a physiological
role of pendrin in mediating iodide efflux
clear that iodide is indeed the preferred anion and that
SLC26A4 transports iodide in the presence of high
chloride, and that it also mediated luminal iodide secretion
in parotis gland ducts [41]. Moreover, the results conducted in polarized cells have been performed under physiological concentrations of iodide and chloride and suggest
that pendrin preferentially mediates iodide efflux [39].
Similar conclusions have been drawn from electrophysiological studies with variable extracellular iodide and
chloride concentrations [38]. These data also suggest that
iodide efflux/chloride influx is more efficient than chloride
efflux/chloride influx [38]. It has also been argued that
the distinct role of pendrin in the thyroid as a putative
iodide/chloride exchanger is intriguing given its function
as a chloride/bicarbonate exchanger in the inner ear and
the kidney [5, 6, 63, 64]. The differential role may, however,
depend on the relative anion concentrations in the respective cells and thyroid cells distinguish themselves by unusually high iodide concentrations due to the expression of
NIS [12]; this, and the preference of SLC26A4 for iodide
over chloride, should thus result in iodide efflux into the
follicular lumen analogous to findings obtained in the
parotis ducts [41].
Given that the vast majority of patients with biallelic
mutations in the SLC26A4 gene have only a mild or no
thyroidal phenotype under normal iodide intake conditions
[30], one or several other channels and/or transporters
seem to be involved in the apical efflux of iodide into the
follicular lumen. Their identity is currently unknown.
SLC5A8, originally designated as human apical iodide
transporter (hAIT) [65], is not involved in mediating iodide
efflux as demonstrated by functional studies in Xenopus
oocytes and polarized MDCK cells [66]. Interestingly,
mice with targeted disruption of the CLCN5 chloride
channel, which is localized at the apical membrane of
thyrocytes, develop a thyroidal phenotype that is reminiscent of Pendred syndrome with goiter formation and
decreased iodide organification [67]. In humans, CLCN5
is mutated in the X-linked recessive Dent’s disease (hypercalcuric nephrolithiasis, proteinuria/aminoaciduria, glyco-
suria; OMIM 300008), which is not associated with a
thyroidal phenotype. Further functional studies are needed
to characterize the potential role of CLCN5 in terms of
iodide transport. Interestingly, in thyroid tissue from a
patient with Pendred syndrome, the absence of pendrin
was accompanied by increased CLCN5 expression [68],
and it has been speculated that this may compensate for
apical iodide efflux.
It is noteworthy that studies in the Slc26a4 -/knockout mouse have shown that the transepithelial
potential and the pH of thyroid follicles are reduced [69],
suggesting that pendrin-mediated bicarbonate efflux into
the follicle and chloride uptake into thyrocytes is diminished.
Hence, it is conceivable that a change in intrafollicular
pH could result in impaired organification of iodide, for
example by reducing the efficiency of thyroid peroxidase.
Conclusion
Patients with Pendred syndrome have a mildly
impaired iodide organification defect and they can present
with goiter and more rarely with hypothyroidism. Based
on studies in frog oocytes and mammalian cells, it is clear
that pendrin has a higher affinity for iodide than for chloride
and bicarbonate, and that it is able to mediate apical iodide
efflux in polarized cells. Moreover, pendrin membrane
abundance and iodide efflux appear to be stimulated by
TSH in rat thyroid cells. Apical iodide efflux is, however,
also possible in the absence of pendrin implicating the
presence of at least one additional iodide transporting
entity. In addition, it is conceivable that the impaired organification could result from an alteration in follicular pH.
Addressing these persisting controversies should
permit to better establish the role of pendrin in the
pathophysiology of the thyroid gland in the near future.
Acknowledgements
The publication of this review has been supported
by a gift from Mr. David Wiener to PK.
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