Download potassium channels as a novel target in thyroid diseases

POTASSIUM CHANNELS AS A NOVEL TARGET IN
THYROID DISEASES
6:3
Madhukar Rai, Amit Agarwal, Varanasi
Abstract
Voltage gated Potassium channels has long been recognized as important for function of excitable cell
such as electrical signalling in the brain and rhythmic beating of the heart. These cells generate action
potentials, which require voltage-gated sodium (NaV) channels for the depolarization phase (upstroke)
and voltage-gated potassium (KV) channels for the repolarization phase (downstroke). Recently, ion
transporters have been demonstrated on basolateral part of thyrocytes. Potassium channel subunits
KCNQ1 and KCNE2, form a thyroid-stimulating hormone (TSH) –stimulated, constitutively active,
thyrocyte K+ channel required for normal thyroid hormone biosynthesis and are essential for iodine
trapping by Na+/I- symporter (NIS). This has led to new areas of intervention and opened new targets
for treatment for thyroid diseases.
Introduction
Thyroid hormones (TH), thyroxine (T4) and triiodothyronine (T3) are crucial for proper growth and
development. Both the excess and the lack of these hormones can lead to various manifestations,
some of them even fatal if not recognised early. They play an integral role in maintenance of cognitive
function, body metabolism and cardiac function. In addition, iodide deficiency required for thyroid
hormone synthesis manifests most severely during pregnancy when then demand for TH increases.
Inability to supply the growing fetus with TH can result in fetal mortality, defect in neuronal myelination
and synapse formation, retarded growth and mental retardation.
Excitable cells facilitate dynamic processes such as electrical signalling in the brain and rhythmic
beating of the heart. Excitability, defined in this context as the ability to sustain action potentials,
requires voltage-gated sodium (NaV) channels for the depolarization phase and voltage-gated
potassium (KV) channels for the repolarization phase. For example in cardiac tissues, most prominent
repolarisation phase, Phase 3, is coordinated primarily by two Kv α subunits: hERG and KCNQ1,
which respectively generate the (fast)Ikr and (slow)Iks repolarisation potassium currents.1,2
Potassium Channels and thyroid dysfunction
KCNQ1 and hERG constitute α subunits of potassium channels consisting of six transmembrane
helices within which is a voltage sensor that moves after membrane depolarisation , making the channel
to permit ion flux. However they do not function alone. They form complexes with KCNE β subunits,
also referred to as Mink –related peptides (MiRPs).3,4 KCNE subunits are single transmembrane
segment (TMS) proteins that do not pass current alone, but co-assemble with pore-forming Kv subunits
to regulate their trafficking, gating, conductance, regulation by other proteins, and pharmacology.
(Fig 1)
KCNQ1 has a property unique among Kv subunits: it can be converted to a constitutively open K+
leak channel (i.e., one that does not require membrane depolarization to open) by co assembly with
the KCNE2 or KCNE3 ancillary subunits.5,6 While it is not yet known whether KCNQ1 forms leak
channels in human heart with KCNE2 or KCNE3, the ability to open constitutively has been shown to
facilitate functional roles for KCNQ1-KCNE complexes in non-excitable, polarized epithelia in vivo.
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Fig. 1 : KCNE2 and KCNQ1. (A) Topology of KCNQ1 and KCNE2 with respect to the cell membrane. (B) Idealized cutaway lateral
view of a KCNQ1-KCNE2 complex (KCNQ1,grey; KCNE2, red). (C) Cartoon lateral view of a KCNQ1-KCNE2 channel complex,
stoichiometry as determined for KCNQ1-KCNE1 (Chen et al., 2003a). (D) Cartoon top view of a KCNQ1-KCNE2 complex suggesting a
possible juxtaposition of the two subunit types.
In gastric parietal cells, KCNQ1-KCNE2 channels provide an
apical K+ recycling pathway required for gastric acidification
by the apical gastric H+/K+ATPase7,8,9. In the colon, basolateral
KCNQ1-KCNE3 channels help provide a driving force for
cAMP stimulated Cl− secretion10.
Fig. 2 : The putative role for KCNQ1-KCNE2 (blue) in thyrocytes
is to facilitate K+ efflux basolaterally. A subset of other channels
and transporters are shown for context: Kir7.1, inward rectifier K+
channel; NKA, Na+/K+/ATPase; NIS, Na+/I− symporter (yellow). At the apical membrane, I− passes from the thyrocyte to the
colloid for organification, through pendrin or another, unspecified
protein (yellow), resulting in formation of thyroglobulin (Tg)
Roepke et al 11 have found KCNQ1-KCNE2 channels in
thyroid follicular cells in the basolateral membrane and their
role in iodide accumulation and normal thyroid hormone
biosynthesis. The Na+/I- symporter (NIS) is responsible for
the accumulation of I- in thyrocytes in the first step of TH
biosynthesis. I- is then transported apically into the colloid
in the thyroid lumen where it is organified into thyroglobulin
(Tg) and subsequently incorporated into T3 and T4. NIS
uses the movement of Na+ down its concentration gradient to
accumulate I- into thyrocytes. While it has previously been
established that the Na+/K +ATPase, which co-localizes with
NIS at the basolateral membrane, generates this gradient by
pumping Na+ out in exchange for moving K+ in 12, the pathway
responsible for moving K+ back out of the cell has remained
enigmatic. Recent findings show that KCNE2, probably
primarily in complexes with KCNQ1, is required for normal
I- accumulation in the thyroid, suggesting that the KCNQ1KCNE2 channel may form the aforementioned thyrocyte K+
efflux pathway. (Fig 2)
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Potassium Channels as a Novel Target in Thyroid Diseases
Evidences and clinical implications
Targeted disruption of Kcne2 in mice impaired thyroid
iodide accumulation up to eightfold, impaired maternal milk
ejection, halved milk tetraiodothyronine (T4) content and
halved litter size. Kcne2-deficient mice had hypothyroidism,
dwarfism, alopecia, goiter and cardiac abnormalities including
hypertrophy, fibrosis, and reduced fractional shortening. The
alopecia, dwarfism and cardiac abnormalities were alleviated
by triiodothyronine (T3) and T4 administration.11 These
data provide a new potential therapeutic target for thyroid
disorders and raise the possibility of an endocrine component
to previously identified KCNE2- and KCNQ1-linked human
cardiac arrhythmias.
Subclinical hypothyroidism is also associated with prolonged
QTc13 interval, seen with loss-off-function mutations in
KCNE2 and KCNQ114, 15. Around 13% of patients with
idiopathic AF have evidence of hyperthyroidism16; in one
study, 62% of 163 patients reverted to sinus rhythm when
treatment for hyperthyroidism returned them to a euthyroid
state17. Lone familial atrial fibrillation has been shown to be
associated with gain-of function mutations in KCNE2 and
KCNQ1.18, 19
Mutations in voltage gated potassium channels are associated
with cardiac arrhythmias (KCNQ1 AND KCNE2 channels)
20, 21
. Loss of function mutations in KCNQ1 result in long QT
syndrome type 1 (LQTS 1), sub-classified as Romano-Ward
Syndrome (autosomal dominant) and Jervell Lange Nielsen
Syndrome (autosomal recessive). Chen et al22 and Yang et
al19 found that gain-of-function mutations in KCQN1 appear
to underlie some cases of lone atrial fibrillation. KCNE2
mutations are associated with inherited and drug induced
LQTS, classified as LQTS6. These findings along with the fact
that thyroid dysfunction also is associated with the prolonged
QTc interval and atrial fibrillation lead to the researchers to
find the role of potassium channels in thyroid metabolism .
Roepke et al 11demonstrated that KCNQ1-KCNE2 channels
are expressed in human and rodent thyrocytes, where they
generate a TSH-stimulated, constitutively-active K+ current.
They found that KCNE2-/- mice had cardiomegaly, dwarfism
and alopecia, the findings which are known to be found in
congenital hypothyroidism 23. They generated a hypothesis
that the KCNE2-/- disruption lead to hypothyroidism in these
mice. To prove this they found that indeed the T4 level was 2
fold decreased and thyroid stimulating hormone (TSH) was
2 fold increased in KCNE2-/- compared to KCNE2+/+ mice.
Further when these KCNE2-/- pups were surrogated with
KCNE2+/+ dams in pre weaning period they regained normal
body weight. Conversely, pre-weaning surrogacy of KCNE2+/+
pups with KCNE2−/− dams resulted in mean pre-weaning
body weight similar to KCNE2−/− pups. These data suggested
the possibility that maternal TH passing through milk from
wild-type dams were compensating for the defect in pups.
Further when thyroid hormones were replaced in KCNE2pups, alopecia, cardiac dilatation, body weight improved.
Thus they further hypothesised that KCNE2 channels had
a role in thyroid hormone synthesis. They detected KCNQ1
and KCNE2 proteins in FRTL5 cell membrane fractions
and which appeared to be upregulated by TSH and its major
downstream effector cAMP. They then measured endogenous
currents from FRTL5 cells using patch-clamp recording in
the whole-cell configuration and found that a TSH-stimulated
K+ current in FRTL5 cells bore the signature linear currentvoltage relationship of KCNQ1-KCNE2 channels and was
inhibited by the KCNQ-specific antagonist XE991. In
sum, these findings proved that KCNQ1-KCNE2 channels
are expressed in human and rodent thyrocytes, where they
generate a TSH-stimulated, constitutively-active K+ current.
/-
Conclusion
Despite there being a long-recognized link between thyroid
dysfunction and cardiovascular risk, and an awareness
that THs regulate expression of K+ channels in the heart ,
recent discovery of a crucial role for KCNE2 and KCNQ1
in TH biosynthesis presents a novel and unexpected genetic
link between thyroid dysfunction and cardiac arrhythmias.
Mutations in KCNE2 and/or KCNQ1 have previously been
associated with LQTS, AF, and even early-onset myocardial
infarction19-22, each of which is also predisposed to by thyroid
dysfunction in the general population, suggesting the intriguing
possibility of an endocrine component to some KCNE2- and
KCNQ1-associated human cardiac disease. Whether or not the
discovery of KCNQ1-KCNE2 in the thyroid and its role in TH
biosynthesis leads to use of KCNQ1-KCNE2 modulators to
treat thyroid dysfunction remains to be seen, but these findings
should at least be a consideration in future studies of thyroidrelated cardiac disease, its molecular etiology and therapy.
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