© 1997 American Heart Association, Inc.
Articles |
Two Isoforms of the Mouse Ether-a-go-go–Related Gene Coassemble to Form Channels With Properties Similar to the Rapidly Activating Component of the Cardiac Delayed Rectifier K+ Current
From the Division of Cardiology (B.L., K.P.N., A.K.B.), University of Pittsburgh (Pa) Medical Center; the Department of Physiology (M.C.T., G.A.R.), University of Wisconsin Medical School, Madison; the Mammalian Genetics Laboratory (N.G.C., D.J.G., N.A.J.), ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Md; and the Central Research Division (C.A.S.), Pfizer Inc, Groton, Conn.
Correspondence to Barry London, MD, PhD, Division of Cardiology, University of Pittsburgh Medical Center, BST 1744, 200 Lothrop St, Pittsburgh, PA 15213-2582. E-mail london{at}card2.cath.upmc.edu
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Abstract |
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Abstract HERG, the human ether-a-go-go–related gene, encodes a K+-selective channel with properties similar to the rapidly activating component of the delayed rectifier K+ current (IKr). Mutations of HERG cause the autosomal-dominant long-QT syndrome (LQTS), presumably by disrupting the normal function of IKr. The current produced by HERG is not identical to IKr, however, and the mechanism by which HERG mutations cause LQTS remains uncertain. To better define the role of Erg in the heart, we cloned Merg1 from mouse genomic and cardiac cDNA libraries. Merg1 has 16 exons and maps to mouse chromosome 5 in an area syntenic to human chromosome 7q, the map locus of HERG. We isolated three cardiac isoforms of Merg1: Merg1a is homologous to HERG and is expressed in heart, brain, and testes, Merg1a' lacks the first 59 amino acids of Merg1a and is not expressed abundantly, and Merg1b has a markedly shorter divergent N-terminal cytoplasmic domain and is expressed specifically in the heart. The Merg1 isoforms, like HERG, produce inwardly rectifying E-4031–sensitive currents when heterologously expressed in Xenopus oocytes. Merg1a and HERG produce currents with slow deactivation kinetics, whereas Merg1a' and Merg1b currents deactivate more rapidly. Merg1b coassembles with Merg1a to form channels with deactivation kinetics that are more rapid than those of Merg1a or HERG and nearly identical to IKr. In addition, a homologue of Merg1b is present in human cardiac and smooth muscle. Thus, we have identified a novel N-terminal Erg isoform that is expressed specifically in the heart, has rapid deactivation kinetics, and coassembles with the longer isoform in Xenopus oocytes. This N-terminal Erg isoform may determine the properties of IKr and contribute to the pathogenesis of LQTS.
Key Words: K+ channel • coassembly • long-QT syndrome • rapidly activating component of delayed rectifier K+ current • HERG
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Introduction |
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The human ether-a-go-go–related gene, HERG, was originally cloned by homology to the Drosophila K+ channel gene eag.1,2 It has six putative membrane-spanning domains (S1 to S6), a conserved putative pore domain, and a putative CNB domain. HERG is known to contain introns,3 but the entire gene structure has not been published. It is expressed abundantly in cardiac atrial and ventricular tissues of many mammalian species.4,5 When expressed in Xenopus oocytes, HERG channels produce an inwardly rectifying K+-selective current that is blocked by methanesulfonanilides, such has E-4031 or dofetilide, and is enhanced by extracellular K+.6,7 The inward rectification of HERG is due to a fast inactivation mechanism with similarities to C-type inactivation in Shaker.8,9
IKr is one component of the delayed rectifier K+ current that contributes to the repolarization phase of the mammalian cardiac action potential. IKr has been identified and characterized in atrial and ventricular myocytes from several mammalian species, including mice and humans.4,10-17 Electrophysiological and pharmacological similarities between IKr and the currents produced by HERG channels in vitro have led to widespread acceptance of the hypothesis that Erg channels produce IKr.6,7,18-20 The deactivation kinetics of IKr in mouse AT-1 cells13 and guinea pig ventricular myocytes,10 however, are significantly faster than those of HERG channels expressed in Xenopus oocytes or mammalian cell lines. Along with a recent report suggesting that HERG subunits may associate with other channel polypeptides,21 these findings suggest that the relationship of HERG to IKr is not fully understood, and a role for other channel subunits in IKr remains possible.
Mutations of HERG cause the autosomal-dominant LQTS (Romano-Ward syndrome) in families in which the affected individuals are linked to the LQT2 locus on human chromosome 7q35-q36.3 LQTS was first described in the early 1960s and is characterized clinically by recurrent syncope, a prolonged QT interval with an abnormal T-wave morphology on the surface ECG, torsade de pointes (polymorphic ventricular tachycardia with a rotating axis), and sudden death.22 The exact mechanism by which mutations of HERG subunits cause LQTS remains uncertain.
A more complete understanding of HERG is essential to the understanding of its role in the electrophysiology of the normal heart and the pathophysiology of disease. We report in the present study the cloning of Merg1, the mouse homologue of HERG, the characterization of its gene structure, and the identification of a novel cardiac-specific N-terminal truncated isoform that may contribute to the cardiac current IKr.
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Materials and Methods |
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Cloning of Merg1
Standard methods for library screening and molecular cloning were used.23 Using a radiolabeled PCR-generated fragment from the hydrophobic core of HERG (T7 QuickPrime, Pharmacia Biotech), we screened mouse and human heart cDNA libraries (Stratagene) and isolated a partial-length mouse cDNA clone homologous to HERG (CM3), which was
3550 bp in length and extended to the poly-A tail. We
rescreened the mouse library with a more 5' fragment cloned from the
human cDNA library and identified an 750-bp cDNA clone (CMH2), which
started 40 nucleotides downstream from the putative
start codon of HERG, and an 990-bp cDNA clone (CMH1) that had a
novel 95 bp at its 5' end and was then homologous to HERG, starting
75 nucleotides downstream from the putative start codon
of HERG. Using the inserts of CMH2 and CM3 as templates for randomly
primed probes, we then screened the mouse heart library and identified
a full-length clone homologous to HERG (H1, 4215 bp, designated
Merg1a) and a second shorter clone with a novel 5' end (H7, 3135 bp,
designated Merg1b). Both H1 and H7 contain in-frame stop codons in the
5' untranslated region. RACE (indicating rapid amplification of cDNA
ends) was performed using nested antisense primers in exon 6, which is
common to both isoforms (GIBCO-BRL). A clone that extended 30
nucleotides further upstream than the H7 cDNA clone was
isolated; the extra nucleotides correspond to the genomic
clone (see below). All cDNA clones were double-strand–sequenced.
Using PCR and cDNA fragments of HERG and Merg1a, we screened an
SV129 mouse genomic library (
-FIX, Stratagene) and isolated several
genomic clones, of which two were subcloned and sequenced. The first,
Me3, contained exons 3 through 15 (including exon 1b); the second,
2GMBg6, contained exons 1a, 1a', and 2. There was no overlap detected
between the clones, and the size of the gap between exons 2 and 3 is
not known. With the exception of this gap, the portion of each clone
between exons 1 and 15 was single-strand–sequenced; all exons and the
regions flanking the exons were double-strand–sequenced. Eight
nucleotide differences were detected between the cDNA and
genomic clones of Merg1, of which five caused changes in the amino acid
sequence (Fig 1
). We also isolated and
single-strand–sequenced the exons from two human genomic clones that
contained HERG exons 1 through 6.
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Mapping of Merg1 to Mouse Chromosome 5
Interspecific backcross progeny were generated by mating
(C57BL/6JxMus spretus) F1 females and C57BL/6J
males as described by Copeland and Jenkins.24 A total of
205 N2 mice were used to map the Merg1 locus. DNA was
isolated, digested with several enzymes, and analyzed by
Southern blot hybridization for informative RFLPs.25 Blots
were prepared with Hybond-N+ nylon membrane (Amersham). The
3' untranslated region probe, an 600-bp Sac I fragment of
the mouse genomic clone, was labeled using a random-primed kit
(Stratagene) and washed to a final stringency of 0.8x SSC and 0.1%
SDS at 65°C. A fragment of 23 kb was detected in Sca
I–digested C57BL/6J DNA, and a fragment of 8.0 kb was detected in
Sca I–digested M spretus DNA. The presence or
absence of the 8.0-kb Sca I–digested M
spretus–specific fragment was followed in backcross mice. A
description of the probes and RFLPs for the loci linked to
Merg1, including Gnail, En2, and
Il6, has been reported previously.26
Recombination distances were calculated as described27
using the computer program SPRETUS MADNESS. Gene order was determined
by minimizing the number of recombination events required to explain
the allele distribution patterns. We also compared our
interspecific map of chromosome 5 with a composite mouse linkage map
that reports the map location of many uncloned mouse mutations
(provided from Mouse Genome Database, a computerized database
maintained at The Jackson Laboratory, Bar Harbor, Me).
Construction of Merg1 Isoform Expression Vectors
The expression construct for Merg1a was made by subcloning
fragments of clones CM3 and CMH2 into the expression vector pGH19K and
adding either a 5' fragment of clone H1 or a PCR-generated 5' fragment
containing a consensus Kozak sequence
(TCCGCCACCATG)28 at the putative initiator
methionine (Merg1a). The Kpn I site in exon 3 was used for
subcloning. pGH19K is a modification of the pGEMHE
vector.29 The expression clone for Merg1a' was constructed
using clones CM3 and CMH1. The expression clone for Merg1b was
constructed by replacing the 5' end of the Merg1a expression vector
with either the 5' end of clone H7 (Merg1bK-) or with a
PCR-generated fragment containing a consensus Kozak sequence at the
putative initiator ATG codon (Merg1b). The Spe I site in
exon 9 was used for subcloning. Pfu polymerase (Stratagene) was used
for PCR, and artifacts were excluded in all constructs by double-strand
sequencing.
Oocyte Preparation and Electrophysiology
Xenopus oocytes were isolated and injected with RNA
as described previously,7,30 except that some oocytes were
defolliculated using osmotic shock, a technique that expedites the
defolliculation procedure.31 No differences in
electrophysiological responses were
observed using the two methods. RNA was synthesized in vitro from the
T7 promoter of the Merg1 cDNA expression constructs using the Message
Machine kit (Ambion). The different clones exhibited markedly different
expression levels. Because our goal was to compare different isoforms
at similar expression levels, we "calibrated" individual
transcription reactions according to expression level and diluted the
RNA to a concentration that would produce currents in the range of 0.5
to 8.0 µA to ensure excellent voltage-clamp control. For
coexpression, half the solution volume of each RNA species at 2x
concentration used for independent expression was mixed and
injected.
Currents were recorded with a two-electrode voltage clamp (OC-725C,
Warner). Recording electrodes were made with a Sutter P-97
micropipette puller (Novato) from borosilicate glass (World Precision
Instruments) and had resistances of 0.5 to 1.0 M
when filled with 2
mol/L KCl. Data acquisition and analysis were performed
using pClamp6 (Axon Instruments) and Origin4 software (Microcal).
Experiments were performed at room temperature (22°C to 24°C).
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Results |
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Three Isoforms of Merg1 Cloned From the Mouse Heart
We cloned Merg1, the mouse ether-a-go-go–related gene, from a mouse heart cDNA library (Stratagene) and identified three cDNA isoforms. Fig 1
shows the amino
acid sequences of the isoforms aligned with the previously published
HERG sequence. Merg1a, the longest isoform, has an 1162–amino acid
open reading frame and is 96% identical to HERG at the amino acid
level. There is >99% identity between Merg1a and HERG in the region
between the S1 and CNB domains. Merg1a' has an alternate 5' untranslated region and is identical to Merg1a from amino acid 25 onward. The alternate 5' end has an in-frame stop codon and no downstream translation initiation codon. This requires that translation begin at or downstream from the second in-frame ATG codon of Merg1a, and the Merg1a' channel thus lacks the first 59 amino acids of Merg1a.
Merg1b, the shortest isoform, has an 820–amino acid open reading frame, is identical to Merg1a from S1 to the carboxy-terminal end, and has a novel, markedly shorter amino-terminal cytoplasmic domain. The 36 amino acids at the amino-terminal end of Merg1b show no significant homology to any previously cloned genes and lack a number of the consensus protein kinase phosphorylation sites found in Merg1a.
Structure and Location of MERG1
Fig 2A shows the genomic
organization of Merg1, including the location of the exons and the
alternate isoforms. Two closely related polyadenylation sites
correspond to two 3' untranslated regions identified on cDNA clones.
Merg1a is encoded by 15 exons and spans >25 kb of genomic DNA. MERG1a'
appears to use an alternate exon-1 splice donor site that is 226
nucleotides downstream from the site used by the Merg1a
isoform. Merg1b, on the other hand, has a different first exon
(designated 1b), which is located between exons 5 and 6 of Merg1a. The
regions immediately upstream from both exons 1a and 1b are extremely GC
rich, with each containing three SP1 sites. The region upstream from
exon 1b (between exons 5 and 6) may contain an alternate transcription
initiation site that is used for the Merg1b isoform.
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The chromosomal location of Merg1 was determined using
interspecific backcrosses and is shown schematically in Fig 2B.
Merg1 is linked to the loci Gnail,
En2, and Il6 on the proximal part of mouse
chromosome 5; this region shares homology with human chromosome
7q35-q36, the map locus of HERG.3 No mouse
mutations linked to this area of chromosome 5 have a phenotype
that might be expected for an alteration in the Merg1
locus.
Tissue Expression of the Merg1 Isoforms
Tissue-specific RNA expression of the Merg1 isoforms was
determined using exon-specific probes on a mouse multitissue Northern
blot and is shown in Fig 3. Probes from
the 3' end of Merg1 in the region common to all three isoforms
hybridized to a 4.4-kb transcript, which is abundant in heart, brain,
and testes, along with a 3.4-kb transcript, which is abundant only in
the heart. Probes upstream of exon 5 yielded only the larger 4.4-kb
transcript in heart, brain, and testes. A probe specific for Merg1a'
did not hybridize abundantly to RNA from any of the tissues tested
(data not shown). A probe specific for Merg1b yielded the smaller
3.4-kb transcript, which is abundant only in the heart. Thus, Merg1b is
expressed in a cardiac-specific manner and is likely coexpressed with
Merg1a in mouse cardiac myocytes, although we cannot exclude the
possibility of nonoverlapping expression of the two isoforms in
different cells within the heart.
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N-Terminal Isoforms of HERG
Human muscle may also contain at least one other N-terminal
isoform of HERG. A region between exons 5 and 6 of HERG is
homologous to exon 1b of Merg1 (>90% identity at the
nucleotide level). Other intronic regions of the
HERG genomic clone, including the area corresponding to exon
1a' of Merg1, show much less conservation. Fig 1 shows the
sequence of the putative human homologue of Merg1b (HERGb). Northern
blots probed with a DNA fragment from the 3' end of Merg1 show a 4.4-kb
transcript in RNA from human brain, heart, and smooth muscle along with
a 4.0-kb transcript specific to the heart (see Reference 33 ) and a
3.4-kb transcript in cardiac and smooth muscle. Reprobing the blot with
a fragment from human exon 1b confirms low levels of expression of the
shorter isoforms in human cardiac and smooth muscle tissues (data not
shown).
Heterologous Expression of the Merg1 Isoforms in
Xenopus Oocytes
Expression of the Merg1 isoforms in Xenopus produces
currents with pronounced inward rectification (Fig 4A to 4C) similar to those produced by
HERG.6,7 The outward current amplitude declines at more
positive voltages as a consequence of rapid inactivation, giving rise
to the hallmark negative slope conductance on the current-voltage plot
(Fig 4D). On repolarization, the channels first recover from
inactivation and then deactivate (close), producing a
"hook" in the tail current. The most apparent difference among the
isoforms is the rate of deactivation of this tail current (see
below).
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The marked variability in the levels of current expression between the
isoforms was useful in demonstrating that Merg1a and Merg1b coassemble
to form heteromultimers in oocytes (Fig 5A to 5D). A Merg1b construct that lacked
an upstream Kozak consensus sequence (Merg1bK-) did not
produce measurable currents (Fig 5B). However, on coexpression of
Merg1bK- with Merg1a (Fig 5C), the resulting currents had
deactivation kinetics that were faster than those of Merg1a expressed
alone (Fig 5A). Thus, Merg1bK- expression can be rescued
by coassembly with Merg1a and contributes significantly to the
deactivation rate in the heteromer. The construct Merg1b, which
contains a consensus Kozak sequence before the initiator methionine,
expressed currents independently (Figs 4C and 5D). When Merg1b was
coexpressed with Merg1a, the resulting deactivating tail currents
exhibited intermediate kinetics and could not be predicted by the sum
of any ratio of tail currents from homomeric Merg1b and Merg1a channels
(Fig 5E). This supports the conclusion that Merg1a and Merg1b
coassemble to form heteromultimeric channels with
novel gating properties.
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fast)+(A2e-t/
The rapid deactivation kinetics of the short Merg1 isoforms and
Merg1a/Merg1b heteromers are similar to those of native
IKr (Fig 6).
Two-exponential fits to the deactivating tail currents of the Erg
isoforms show that Merg1a and HERG have similarly slow deactivation
kinetics (Fig 6A and 6E to 6G). In contrast, the tail currents of
Merg1a', Merg1b, and Merg1a/Merg1b heteromeric channels decay faster
and are more like those of IKr measured from
mouse AT-1 cells (Fig 6B to 6D, 6F, and 6G), a model system for native
cardiac currents in the mouse.13
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The shorter N-terminal isoforms Merg1a' and Merg1b mimic the fast
deactivation kinetics of HERG N-terminal deletions.8,32 Our
findings provide a physiological counterpart to the
deletion mutants and help to delineate a domain within the N-terminus
important in modulating deactivation. Merg1a' lacks only the first 59
amino acids of Merg1a, thus restricting the region modulating
deactivation to the extreme N-terminus (Fig 6H).
Like HERG channels, Merg1 isoforms and heteromers expressed in
oocytes are blocked by the methanesulfonanilide E-4031. Figs 7A to 7C show the responses of Merg1a,
Merg1b, and heteromeric Merg1a/1b currents evoked at 20 mV to 5
mmol/L E-4031. Dose-response curves indicate a similar range of
sensitivity among the different Merg1 isoforms (Fig 7D) and
HERG.7,18
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have cloned three isoforms of Merg1 from the mouse heart and expressed them heterologously in Xenopus oocytes. Merg1a is structurally and functionally homologous to HERG. Merg1a' lacks the first 59 amino acids of Merg1a and has the rapid deactivation kinetics characteristic of N-terminal deletions of HERG.8,32 This suggests that one area of the channel that modulates the deactivation kinetics lies in these first 59 amino acids and likely requires translation of exon 1a. Merg1b begins at an alternate site downstream in the gene, has an N-terminal cytoplasmic domain that is distinct from that of Merg1a, and is expressed in a cardiac-specific manner. Western blots have raised the possibility of other ERG isoforms,33 but their size and tissue distribution are not consistent with Merg1b. Merg1b has rapid deactivation kinetics when expressed in Xenopus oocytes and coassembles with Merg1a to form heteromeric channels with rapid deactivation kinetics. Although a specific region of the N-terminal cytoplasmic domain of HERG has been shown to play a role in HERG subunit assembly,34 our results show that other sequences or domains must also control assembly of Merg1b into homomers and heteromers.
Merg1b expression levels in Xenopus oocytes were markedly lower than those of Merg1a. Although we cannot be certain that injection of similar amounts of RNA for each isoform produces similar quantities of channel protein, this finding may indicate that polypeptides containing shorter or truncated N-termini are less stably assembled as functional homomeric channels. In addition, Merg1b expression results in measurable currents only when the putative translation initiation site is preceded by a Kozak consensus sequence. This discrepancy may by explained by a lower expression level of the Merg1bK- construct, as would be expected in the absence of the Kozak consensus sequence. Alternatively, translation of the Merg1bK- construct may be initiated at AUG codons which lie downstream to amino acid 59 and result in even shorter isoforms. However, constructs both with and without the Kozak consensus sequence are apparently expressed sufficiently to coassemble with Merg1a and form heteromeric channels.
IKr generally has rapid deactivation kinetics.4,10-15,17 Rapid deactivation of IKr is essential for maintaining electrical excitability and homogeneity, especially at the high heart rates normally found in the mouse. Coexpression of Merg1b and Merg1a produces channels with deactivation kinetics that are much faster than those recorded for Merg1a or HERG alone and that match the physiological profile of IKr for mouse myocytes.13 This, along with the simultaneous expression of both isoform transcripts in the heart, supports the hypothesis that Merg1a and Merg1b coassemble in vivo to form the channel responsible for IKr in the mouse.
Differences in IKr deactivation kinetics have been reported between species.16 Our findings provide a plausible explanation for this variability in the properties of IKr. N-terminal truncated isoforms of Erg may be expressed at higher levels in cardiac myocytes that have a more rapid deactivation of IKr. Erg isoform expression may also contribute to gender and developmental differences in the QT interval of certain species.
A surprising degree of K+ channel
heterogeneity is found in mammals. Factors contributing
to this heterogeneity include (1) the existence of >50
genes encoding 
-subunits,35-37 (2) alternate splicing of
some K+ channel genes, including KvLQT1, which
also causes LQTS,36,38 (3) coassembly of related
-subunits to form heteromultimers,39-42 and (4)
ß-subunits that modify channel function.43-45 In the
heart, it is likely that subunits encoded by different genes coassemble
to form native channels, such as GIRK1 with CIR to produce the
acetylcholine-sensitive K+ current
(IKAch)46 and KVLQT1 with minK (IsK)
to produce the slowly activating component of the delayed rectifier
K+ current (IKa).47,48
In the present study, we describe coassembly of tissue-specific
alternate isoforms of a single gene to form channels with properties
similar to IKr. Coassembly of Merg1a with Merg1b
produces channels with a unique kinetic profile restricted to the
heart. Along with the examples cited above, our findings emphasize the
caution required when equating a single gene product to a cardiac
current.
The mechanism by which HERG mutations cause LQTS remains uncertain: possibilities include (1) a gene dosage effect, with heterozygotes having inadequate functional channels and outward repolarizing current, and (2) a dominant-negative mechanism, with mutated HERG subunits coassembling with wild-type subunits of HERG and possibly with subunits of related channels to form nonfunctional channels.3,34,49 A recent study showed that not all HERG mutations appeared to act in a dominant-negative manner when mutant and wild-type RNAs were coinjected into Xenopus oocytes.50 The present study suggests that at least two N-terminal HERG isoforms are present in the heart and may be important in determining the mechanism by which mutations cause LQTS. For example, one isoform may act in a dominant-negative manner even though another does not. In addition, although experimental screening bias may contribute, all HERG mutations associated with LQTS are in the region of the channel common to all of the isoforms.3,51-53 Thus, it may be necessary for a mutation to affect all of the isoforms to cause the autosomal-dominant disease phenotype. Alternatively, mutations that affect the expression level or functional properties of a cardiac-specific isoform similar to the one described in the present study may in some cases directly cause LQTS.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by National Heart, Lung, and Blood Institute grants K08 HL-02843 (Dr London) and R01 HL-55793 to 01 (Dr Robertson), a Child Health Research grant from the Charles H. Hood Foundation (Dr London), a predoctoral fellowship (96-F-Pre-23) from the American Heart Association, Wisconsin Affiliate, Inc (M. Trudeau), a gift from the Bayer Corp (Dr Robertson), and funding from the National Cancer Institute, Department of Health and Human Services, under contract with Advanced Bioscience Laboratories Inc (Dr Jenkins). Sequences for the Merg1 clones have been submitted to GenBank under the following accession numbers: AF012868 (Merg1a), AF012869 (Merg1b), and AF012870 and AF012871 (Merg1 genomic clones). We thank Mark R. Vesely and Richard Schell for their technical assistance; Arthur M. Feldman, Jinling Wang, Craig January, and Zhengfeng Zhou for their helpful discussions; Alexandre F. R. Stewart for his comments on the manuscript; and Eisai Research Laboratories (Japan) for their generous gift of E-4031.
Received May 6, 1997; accepted August 29, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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S. Kupershmidt, T. Yang, M. E. Anderson, A. Wessels, K. D. Niswender, M. A. Magnuson, and D. M. Roden Replacement by Homologous Recombination of the minK Gene With lacZ Reveals Restriction of minK Expression to the Mouse Cardiac Conduction System Circ. Res., February 5, 1999; 84(2): 146 - 152. [Abstract] [Full Text] [PDF]
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B. Engeland, A. Neu, J. Ludwig, J. Roeper, and O. Pongs Cloning and functional expression of rat ether-a-go-go-like K+ channel genes J. Physiol., December 15, 1998; 513(3): 647 - 654. [Abstract] [Full Text] [PDF]
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J. Wang, M. C. Trudeau, A. M. Zappia, and G. A. Robertson Regulation of Deactivation by an Amino Terminal Domain in Human Ether-a-go-go -related Gene Potassium Channels J. Gen. Physiol., November 1, 1998; 112(5): 637 - 647. [Abstract] [Full Text] [PDF]
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S. Kupershmidt, D. J. Snyders, A. Raes, and D. M. Roden A K+ Channel Splice Variant Common in Human Heart Lacks a C-terminal Domain Required for Expression of Rapidly Activating Delayed Rectifier Current J. Biol. Chem., October 16, 1998; 273(42): 27231 - 27235. [Abstract] [Full Text] [PDF]
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S. Kaab, J. Dixon, J. Duc, D. Ashen, M. Nabauer, D. J. Beuckelmann, G. Steinbeck, D. McKinnon, and G. F. Tomaselli Molecular Basis of Transient Outward Potassium Current Downregulation in Human Heart Failure : A Decrease in Kv4.3 mRNA Correlates With a Reduction in Current Density Circulation, October 6, 1998; 98(14): 1383 - 1393. [Abstract] [Full Text] [PDF]
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P. Babij, G. R. Askew, B. Nieuwenhuijsen, C.-M. Su, T. R. Bridal, B. Jow, T. M. Argentieri, J. Kulik, L. J. DeGennaro, W. Spinelli, et al. Inhibition of Cardiac Delayed Rectifier K+ Current by Overexpression of the Long-QT Syndrome HERG G628S Mutation in Transgenic Mice Circ. Res., September 21, 1998; 83(6): 668 - 678. [Abstract] [Full Text] [PDF]
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I. M Herzberg, M. C Trudeau, and G. A Robertson Transfer of rapid inactivation and sensitivity to the class III antiarrhythmic drug E-4031 from HERG to M-eag channels J. Physiol., August 15, 1998; 511(1): 3 - 14. [Abstract] [Full Text] [PDF]
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 D. Rampe, M. K. Murawsky, J. Grau, and E. W. Lewis The Antipsychotic Agent Sertindole is a High Affinity Antagonist of the Human Cardiac Potassium Channel HERG J. Pharmacol. Exp. Ther., August 1, 1998; 286(2): 788 - 793. [Abstract] [Full Text]
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 M. Taglialatela, A. Pannaccione, P. Castaldo, G. Giorgio, Z. Zhou, C. T. January, A. Genovese, G. Marone, and L. Annunziato Molecular Basis for the Lack of HERG K+ Channel Block-Related Cardiotoxicity by the H1 Receptor Blocker Cetirizine Compared with Other Second-Generation Antihistamines Mol. Pharmacol., July 1, 1998; 54(1): 113 - 121. [Abstract] [Full Text]
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B. London, D. W Wang, J. A Hill, and P. B Bennett The transient outward current in mice lacking the potassium channel gene Kv1.4 J. Physiol., May 15, 1998; 509(1): 171 - 182. [Abstract] [Full Text] [PDF]
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R. L. Rasmusson, M. J. Morales, S. Wang, S. Liu, D. L. Campbell, M. V. Brahmajothi, and H. C. Strauss Inactivation of Voltage-Gated Cardiac K+ Channels Circ. Res., April 20, 1998; 82(7): 739 - 750. [Abstract] [Full Text] [PDF]
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G. Hofmann, P. A. Bernabei, O. Crociani, A. Cherubini, L. Guasti, S. Pillozzi, E. Lastraioli, S. Polvani, B. Bartolozzi, V. Solazzo, et al. HERG K+ Channels Activation during beta 1 Integrin-mediated Adhesion to Fibronectin Induces an Up-regulation of alpha vbeta 3 Integrin in the Preosteoclastic Leukemia Cell Line FLG 29.1 J. Biol. Chem., February 9, 2001; 276(7): 4923 - 4931. [Abstract] [Full Text] [PDF]
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A. A. Selyanko, P. Delmas, J. K. Hadley, L. Tatulian, I. C. Wood, M. Mistry, B. London, and D. A. Brown Dominant-Negative Subunits Reveal Potassium Channel Families That Contribute to M-Like Potassium Currents J. Neurosci., March 1, 2002; 22(5): RC212 - RC212. [Abstract] [Full Text] [PDF]
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M. Weerapura, S. Nattel, D. Chartier, R. Caballero, and T. E Hebert A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link? J. Physiol., April 1, 2002; 540(1): 15 - 27. [Abstract] [Full Text] [PDF]
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B. London, W. Guo, X.-h. Pan, J. S. Lee, V. Shusterman, C. J. Rocco, D. A. Logothetis, J. M. Nerbonne, and J. A. Hill Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine-Sensitive Component of IK,slow and Resistance to Drug-Induced QT Prolongation Circ. Res., May 11, 2001; 88(9): 940 - 946. [Abstract] [Full Text] [PDF]
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