Functional Expression of Two KvLQT1-related Potassium Channels
Responsible for an Inherited Idiopathic Epilepsy*
Wen-Pin
Yang
,
Paul C.
Levesque
,
Wayne A.
Little,
Mary Lee
Conder,
Pankajavalli
Ramakrishnan,
Michael G.
Neubauer§, and
Michael A.
Blanar¶
From the Department of Cardiovascular Drug Discovery and the
§ Department of Applied Genomics, Bristol-Myers Squibb
Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000
 |
ABSTRACT |
Benign familial neonatal convulsions (BFNC), a
class of idiopathic generalized epilepsy, is an autosomal dominantly
inherited disorder of newborns. BFNC has been linked to mutations in
two putative K+ channel genes, KCNQ2 and
KCNQ3. Amino acid sequence comparison reveals that both
genes share strong homology to KvLQT1, the potassium channel encoded by
KCNQ1, which is responsible for over 50% of inherited long
QT syndrome. Here we describe the cloning, functional expression, and
characterization of K+ channels encoded by
KCNQ2 and KCNQ3 cDNAs. Individually,
expression of KCNQ2 or KCNQ3 in Xenopus oocytes elicits
voltage-gated, rapidly activating K+-selective currents
similar to KCNQ1. However, unlike KCNQ1, KCNQ2 and KCNQ3 currents are
not augmented by coexpression with the KCNQ1
subunit, KCNE1 (minK,
IsK). Northern blot analyses reveal that KCNQ2 and
KCNQ3 exhibit similar expression patterns in different regions within the brain. Interestingly, coexpression of KCNQ2 and
KCNQ3 results in a substantial synergistic increase in current amplitude. Coexpression of KCNE1 with the two channels strongly suppressed current amplitude and slowed kinetics of activation. The
pharmacological and biophysical properties of the K+
currents observed in the coinjected oocytes differ somewhat from those
observed after injecting either KCNQ2 or KCNQ3 by itself. The
functional interaction between KCNQ2 and KCNQ3 provides a framework for
understanding how mutations in either channel can cause a form of
idiopathic generalized epilepsy.
 |
INTRODUCTION |
Potassium channels are the largest and most diverse group of ion
channels. They are primary regulators of resting membrane potential and
action potential configuration and, therefore, modulate excitability of
neurons, cardiac myocytes, and other electrically active cells. Recent
identification of KCNQ1 (KvLQT1), the gene responsible for more than 50% of inherited cardiac long QT syndrome (LQTS),1 established a new
family of six-transmembrane domain K+ channels (1). KCNQ1,
in combination with the KCNE1 subunit, encodes the slow component of
the cardiac delayed rectifier K+ current (2-4), and
mutations in KCNQ1, which occur in LQTS patients, partially or
completely inhibit the channel in a dominant-negative fashion (5, 6).
In an attempt to identify additional members of the KCNQ1
K+ channel gene family, the KCNQ1 sequence was
used to search DNA and protein sequence data banks. Two additional
KCNQ1-related genes, KCNQ2 and KCNQ3,
were identified.
Recent publications indicate that mutations in KCNQ2 or
KCNQ3 are associated with BFNC, an autosomal dominantly
inherited epilepsy in newborns (7-9). Preliminary functional
characterization of KCNQ2 confirmed that this gene encodes a
voltage-activated K+ channel (9). Here we describe the
cloning, tissue distribution, and functional expression of both KCNQ2
and KCNQ3. More importantly, we demonstrate that these two channels
interact functionally with each other and with KCNE1.
 |
EXPERIMENTAL PROCEDURES |
Molecular Cloning and Expression of KCNQ2 and KCNQ3--
5'
Rapid amplification of cDNA ends polymerase chain reaction was
performed by amplifying human brain or fetal brain cDNA libraries
or Marathon-Ready cDNAs (CLONTECH) using
primers derived from the KvLQT1-related EST sequences (EST
numbers yn72g11, yo31c08, and ys93a07). Polymerase chain reaction
products were gel-purified, subcloned, and sequenced. The Gene Trapper
experiment was performed using the protocol as described in the
manufacturer's manual (Life Technologies Inc.). Random-primed
32P-labeled DNA probes containing specific regions of
KCNQ2 or KCNQ3 sequence were used for screening
of cDNA libraries and Northern blot analysis using standard
protocols. The composite full-length KCNQ2 and
KCNQ3 cDNA clones were obtained by restriction enzyme digestion and ligation of overlapping cDNA clones. The full-length cDNAs were subcloned into a Xenopus expression vector,
derived from pSP64T plasmid. Capped cRNA for microinjection was
synthesized using mMessage mMachine Kit (Ambion) as described (4,
6).
Electrophysiology--
Stages V and VI Xenopus
laevis oocytes were defolliculated with collagenase treatment and
injected with cRNAs as described previously (4). Currents were recorded
at room temperature using conventional two-microelectrode voltage clamp
(Dagan TEV-200) 3-4 days after injecting KCNQ2 (15 ng), KCNQ3 (15 ng),
or KCNE1 (2 ng) cRNA alone or in combination. Microelectrodes (0.8 to
1.5 megaohms) were filled with 3 M KCl. Bath solution
contained (in mM): 96 NaCl, 2 KCl, 0.4 CaCl2, 2 MgCl2, and 5 HEPES (pH 7.5). K+ selectivity was
assessed by determining the dependence of tail current reversal
potential on the external K+ concentration. Tail currents
were elicited at potentials of
110 to +10 mV following a voltage step
to +20 mV while the external K+ concentration was varied
between 2, 10, 40, and 98 mM. Current reversal potential
under each condition was determined for each oocyte by measuring the
zero intercept from a plot of tail current amplitude versus
test potential. KCl was varied in selectivity experiments by equimolar
substitution with NaCl. PCLAMP 6.0 software (Axon Instruments) was used
for data acquisition and analysis. All data were sampled at rates at
least two times the low pass filter rate. Clofilium was obtained from
RBI Biochemicals and 4-aminopyridine (4-AP), tetraethylammonium (TEA),
and charybdotoxin were obtained from Sigma. E-4031 was synthesized at
Bristol-Myers Squibb from patents published by Eisai Research
Laboratories.
 |
RESULTS AND DISCUSSION |
Cloning and Tissue Distribution of KCNQ2 and
KCNQ3--
KCNQ1-related expressed sequence tags (ESTs)
were identified in a GCG BLAST search of the GenBankTM data
base with KCNQ1 sequence. Primers, derived from the
consensus sequences of EST clones, were used to amplify human
brain-derived cDNA, and 877-base pair and 325-base pair fragments
were isolated for KCNQ2 and KCNQ3, respectively.
To obtain full-length cDNA sequences of both genes, we employed 5'
rapid amplification of cDNA ends polymerase chain reaction,
screening of cDNA libraries, and Gene Trapper techniques. The
composite full-length cDNAs of KCNQ2 and
KCNQ3 contain an open reading frame (ORF) encoding an 871- and 854-amino acid polypeptide, respectively. DNA sequence analysis and
conceptual translation of both cDNAs reveals that they encode
proteins with the structural features of a voltage-gated potassium
channel and are most closely related to KCNQ1 (3, 4). KCNQ2
exhibits a high degree of sequence similarity with KCNQ3
(
70%), indicating that they belong to the same subfamily. Both
proteins have a longer C-terminal domain (~200 amino acids) than
KCNQ1.
Unlike KCNQ1, which is expressed strongly in human
heart and pancreas (1, 4), Northern blot analysis revealed that
KCNQ2- and KCNQ3-specific transcripts are
detectable only in human brain (Fig. 1).
The sizes of the major transcripts for KCNQ2 and
KCNQ3 are 8.5 kilobases and 10.5 kilobases, respectively.
Expression of human KCNQ2 is high in the hippocampus,
caudate nucleus, and amygdala; moderate in the thalamus, and weak in
the subthalamic nucleus, substantia nigra, and corpus callosum (Fig. 1,
top panel). A separate Northern blot demonstrates
that expression of human KCNQ2 is high in the cerebral
cortex, is moderate in the putamen, temporal lobe, frontal lobe,
occipital pole, and cerebellum, and is barely detectable in the medulla
and spinal cord (Fig. 1, top panel). A similar
pattern of expression was observed previously for KCNQ2 (7).
Interestingly, KCNQ3 exhibits a nearly identical expression
pattern in the brain (Fig. 1, bottom panel).

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Fig. 1.
Expression of KCNQ2 and
KCNQ3 in human tissues and various portions of human
brain. Poly(A+) mRNA Northern blots were
hybridized individually to radiolabeled KCNQ2-specific
(top panel) or KCNQ3-specific
(bottom panel) probes. RNA molecular weight
markers are indicated on the left.
|
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Functional Expression and Characterization of KCNQ2 and
KCNQ3--
The full-length KCNQ2 and KCNQ3 cDNAs were subcloned
into a Xenopus expression vector, and cRNA was generated by
in vitro transcription. The properties of the channels
encoded by KCNQ2 and KCNQ3 were investigated by
expressing the transcribed cRNAs in Xenopus oocytes.
Depolarizing voltage steps elicited outward currents in oocytes
injected with KCNQ2 (Fig. 2A).
The currents activated at potentials positive to
60 mV and showed
slight inward rectification at the more positive potentials. Similar
currents never were observed in water-injected control oocytes. KCNQ2
currents exhibited a rapidly activating delayed rectifier current
phenotype similar to KCNQ1 current (2-4). Fig. 2B shows the
current-voltage (I-V) relationship for KCNQ2 currents recorded at the
end of the 1-s voltage steps. The K+ selectivity of the
expressed current was examined by investigation of tail current
reversal potentials in bath solutions containing 2, 10, 40, and 98 mM K+. Reversal potentials closely followed the
Nernst potential for K+ revealing a predominantly
K+-selective channel (Fig. 2C). The reversal
potential for KCNQ2 current shifted by 51 mV per 10-fold change in
external K+.

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Fig. 2.
Functional and pharmacologic characterization
of KCNQ2 and KCNQ3 currents. A, families of currents
from KCNQ2 cRNA-injected oocytes elicited by 1-s voltage steps, from a
holding potential of 80 mV, to test potentials ranging from 70 to
+50 mV in 10-mV increments. B, current-voltage (I-V)
relationship for oocytes expressing KCNQ2 (n = 6).
Currents were recorded using the protocol in A.
C, dependence of tail current reversal potential
(Erev) on the external K+
concentration. The dashed line has a slope of 58 mV and is drawn according to the Nernst equation for a perfectly
selective K+ channel. Each value is the mean ± S.E.
from 6 oocytes. D, effects of E-4031, 4-AP, TEA,
charybdotoxin, and clofilium on KCNQ2 current. Superimposed currents
were recorded during 1-s steps to +20 mV, from 80 mV, during the same
experiment. Compounds were applied via bath perfusion in order from
top to bottom. The bath was perfused with control
solution for 5 min or until effects reversed completely, between
compounds. Similar results were obtained in three additional oocytes.
E, families of currents from KCNQ3 cRNA-injected oocytes
elicited using the protocol in A. F, I-V
relationship for oocytes expressing KCNQ3 (n = 6).
G, dependence of tail current Erev on
the external K+ calculated using the protocol in
C (n = 6). H, effects of E-4031,
4-AP, TEA, and clofilium on KCNQ3 current. Similar results were
obtained in three additional oocytes.
|
|
Inhibitors of K+ channels were used to investigate the
pharmacology of KCNQ2. The effects of 4-AP, E-4031, clofilium,
charybdotoxin (CTX), and TEA on KCNQ2 currents recorded from a single
oocyte are shown in Fig. 2D. Each of these compounds also
was tested alone in individual oocytes, and the effects of each agent
were consistent with the data shown in Fig. 2. CTX (100 nM), a protein from scorpion venom that inhibits a variety
of Ca2+-activated and voltage-dependent
K+ channels (10, 11), did not inhibit KCNQ2 current. CTX
also had no effect on KCNQ1 current (not shown). E-4031 (10 µM), a selective inhibitor of the HERG K+
channel (12), and 4-AP (2 mM), an inhibitor of Shaker-type K+ channels (13), also had no significant effects on KCNQ2
current. Similarly, neither agent inhibits KCNQ1 channels (4).
Clofilium (10 µM), a compound that inhibits KCNQ1 (4)
with an IC50 <10 µM, had little effect on
KCNQ2 current. TEA (1 mM), a nonselective K+
channel inhibitor and weak KCNQ1 antagonist (4), reduced KCNQ2 current
by 90%.
A family of currents elicited by depolarizing voltage steps in an
oocyte injected with KCNQ3 cRNA are shown in Fig. 2E. The currents activate at potentials positive to
70 mV and rectify inwardly at potentials greater than 0 mV, as is obvious from the I-V
relationship (Fig. 2F). The KCNQ3 reversal potential shifted 49 mV per 10-fold change in external K+ (Fig.
2G). Thus, although still predominantly selective for
K+, KCNQ3 is slightly less K+-selective than
KCNQ2. The pharmacology of KCNQ3 was significantly different from that
of KCNQ2 (Fig. 2H). Clofilium (10 µM) reduced KCNQ3 current by 30% from control but had little effect on KCNQ2. TEA,
which strongly inhibited KCNQ2 at 1 mM, produced little
inhibition of KCNQ3 at 5 mM. CTX (100 nM; not
shown), 4-AP (2 mM), and E-4031 (10 µM) also
had no effect on KCNQ3 current. Thus, although both KCNQ2 and KCNQ3
encode related voltage-activated K+ channels, significant
differences include: (a) degree of rectification at positive
voltages, (b) minimum activation voltage, (c)
selectivity for K+, and (d) pharmacology.
KCNQ2 and KCNQ3 Functionally Interact--
The overlapping
expression pattern of KCNQ2 and KCNQ3 in
different brain regions (Fig. 1), together with the fact that mutations in either KCNQ2 or KCNQ3 cause the same inherited
epilepsy (BFNC; 7-9), prompted us to test for functional interaction
between the two channels. Families of currents elicited by depolarizing
voltage steps in oocytes injected with KCNQ2 and KCNQ3 alone and
together are shown in Fig. 3A.
Current amplitudes recorded from oocytes coexpressing the two channels
were 15-fold greater than in oocytes injected with each of the channels
individually. Peak current amplitudes at +30 mV for KCNQ2, KCNQ3, and
KCNQ2+KCNQ3 were 0.98 ± 0.09 (n = 6), 0.98 ± 0.06 (n = 5), and 14.2 ± 0.62 µM
(n = 6), respectively. Quantitatively similar results
were obtained in three separate batches of oocytes. The I-V
relationship shows that KCNQ2+KCNQ3 currents activated at potentials
positive to
60 mV and did not rectify, unlike KCNQ2 and particularly
KCNQ3, at positive voltages (Fig. 3B). The reversal
potential of tail currents shifted by 57 mV per 10-fold change in
external K+ indicating that KCNQ2+KCNQ3 is nearly perfectly
selective for K+ (Fig. 3C). KCNQ2+KCNQ3 current
is weakly sensitive to inhibition by 5 mM TEA and 10 µM clofilium but not to 100 nM CTX or 2 mM 4-AP (Fig. 3D). E-4031 (10 µM)
also did not inhibit KCNQ2+KCNQ3 current (not shown). These results
suggest strongly that KCNQ2+KCNQ3 interact to form a channel with
properties distinct from either KCNQ2 or KCNQ3 channels.

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Fig. 3.
Coexpression of KCNQ2 and KCNQ3.
A, families of currents from KCNQ2, KCNQ3, and KCNQ2+KCNQ3
cRNA-injected oocytes elicited by 1-s voltage steps, from a holding
potential of 80 mV, to test potentials ranging from 70 to +50 mV
(10-mV increments). B, current-voltage (I-V) relationship
for oocytes expressing KCNQ2+KCNQ3 (n = 6). Currents
were recorded using the protocol in A. C,
dependence of tail current reversal potential
(Erev) on the external K+
concentration. The dashed line has a slope
predicted by the Nernst equation for a perfectly selective
K+ channel. Each value is the mean ± S.E. from 6 oocytes. D, effects of 4-AP, TEA, charybdotoxin, and
clofilium on KCNQ2+KCNQ3 current. Superimposed currents were recorded
during 1-s steps to +20 mV, from 80 mV, during the same experiment.
Compounds were applied via bath perfusion in order from top
to bottom. Similar results were obtained in 4 additional
oocytes.
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minK Interacts with KCNQ2+KCNQ3 Channels--
The
subunit
KCNE1 dramatically alters the amplitude and gating kinetics of the
KCNQ1 channel (2-4, 14). Because KCNQ2 and KCNQ3 are members of the
same K+ channel subfamily, we tested for an interaction
between KCNE1 and KCNQ2+KCNQ3 channels. Fig.
4 shows currents elicited by 1-s depolarizing voltage steps in oocytes expressing KCNE1 alone, KCNQ2+KCNQ3, and KCNQ2+KCNQ3+KCNE1. KCNE1 significantly attenuated KCNQ2+KCNQ3 current amplitude and slowed gating kinetics. Peak current
amplitude at +30 mV was reduced by 62 ± 6.0% (n = 6) in oocytes coexpressing KCNE1. Activating currents were fitted to a bi-exponential function to determine fast and slow time constants of
activation. Fast and slow time constants for activation of KCNQ2+KCNQ3
current at +10 mV were 50.1 ± 3.4 (n = 6) and
239.3 ± 17.5 ms (n = 6), respectively; these were
shifted to 124.7 ± 8.8 (n = 5) and 680.7 ± 71.4 ms (n = 6) when KNCE1 was injected together with
KCNQ2+KCNQ3. Similar results were obtained in more than 15 oocytes from
each group in this and two additional batches of oocytes. KCNE1
currents appear absent because of the duration (1 s) of the voltage
steps used and the scale at which the currents are shown; however, as
shown clearly in the inset, 5-s voltage steps elicited
typical KCNE1 currents in the same oocyte. Whether regions of the brain
which coexpress KCNQ2 and KCNQ3 also express KCNE1 remains to be
determined. The effect of KCNE1 on gating kinetics is similar for KCNQ1
and KCNQ2+KCNQ3 channels. In contrast, KCNE1 augments KCNQ1 current but
inhibits KCNQ2+KCNQ3. Mutations in KCNE1 cause LQTS and
produce dominant-negative suppression of KCNQ1 current (15). Although
KCNE1 has opposite effects on KCNQ1 and KCNQ2+KCNQ3 channels, it will
be interesting to determine whether mutations in KCNE1
account for altered neuronal excitability.

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Fig. 4.
Interaction of KCNE1 with KCNQ2+KCNQ3
currents. Families of currents from KCNE1, KCNQ2+KCNQ3, and
KCNQ2+KCNQ3+KCNE1 cRNA-injected oocytes elicited by 1-s voltage steps,
from a holding potential of 80 mV, to test potentials ranging from
70 to +50 mV (10 mV increments). Inset shows KCNE1
currents elicited by 5-s voltage steps from 80 mV to potentials
ranging from 30 to +50 mV (20-mV increments) in the same oocyte
|
|
The results explain why mutations in either of two unlinked
K+-channel encoding genes yield the same phenotype.
BFNC-associated mutations in either KCNQ2 or
KCNQ3 could cause a profound reduction in KCNQ2+KCNQ3
current amplitude. Interestingly, a BFNC-causing mutation resulting in
an nonfunctional, truncated KCNQ2 protein, failed to produce a
dominant-negative inhibition of wild-type KCNQ2 channels expressed in
oocytes (7). Our results, demonstrating a synergistic interaction
between KCNQ2 and KCNQ3, may provide a likely explanation for this
finding. That is, mutations in KCNQ2 may only produce
dominant-negative effects when coexpressed with wild-type KCNQ3
channels and vice versa. This supports the suggestion from
the previous study (7) that dominant-negative effects of KCNQ2 mutants
may require a
-subunit or second protein. This information will
prove important for the evaluation of functional effects of channel
mutations that cause BFNC and perhaps other disorders of neuronal
excitability.
 |
ACKNOWLEDGEMENTS |
We thank B. Kienzle for DNA sequencing, T. Jenkins-West for oocyte preparation and expert technical assistance,
and W. Koster and D. Hathaway for discussion, comments, and
support.
 |
FOOTNOTES |
*
This work was supported by the Bristol-Myers Squibb
Pharmaceutical Research Institute.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The first two authors contributed equally to this work.
¶
To whom correspondence and reprint requests should be
addressed: Dept. of Cardiovascular Drug Discovery, Mail Code F12-01; Bristol-Myers Squibb Pharmaceutical Research Institute, Route 206 & Provinceline Rd., Princeton, NJ 08543-4000. Tel.: 609-252-4263; Fax:
609-252-6813; Internet: blanar{at}bms.com.
1
The abbreviations used are: LQTS, long QT
syndrome; BFNC, benign familial neonatal convulsions; 4-AP,
4-aminopyridine; TEA, tetraethylammonium; EST, expressed sequence tag;
CTX, charybdotoxin.
 |
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