Differential Distribution of Inward Rectifier Potassium Channel Transcripts in Human Atrium Versus Ventricle
From the Department of Medicine and Research Center, Montreal Heart Institute and University of Montreal, Montreal, Quebec (Z.W., M.W., G.P., S.N.), and the Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec (L.Y., S.N.), Canada.
Correspondence to Dr Zhiguo Wang, Research Center, Montreal Heart Institute, 5000 Bélanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail wangz{at}icm.umontreal.ca
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Abstract |
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Background—The inward rectifier K+ current (IK1) plays an important role in governing cardiac electrical activity and is well known to have different properties in the atrium compared with the ventricle. Several inward rectifier K+ channel (IRK) subunits (hIRK, HH-IRK1, HIR, and TWIK-1) with different properties have been cloned from human tissues, but their relative expression in cardiac tissues has not been quantified. The present study was designed to define the relative levels of mRNA for various IRKs in human atrium and in failing and nonfailing ventricle.
Methods and Results—Competitive reverse transcription–polymerase chain reaction was used to quantify in human atrium and ventricle the mRNA levels of hIRK, HH-IRK1, HIR, and TWIK-1. The absence of important noncardiac contamination was confirmed by demonstrating a lack of detectable mRNA markers for neuronal (acetylcholine receptor) and vascular (maxi-K channel) tissue. mRNA of HIR was more abundant in normal atrium (7.1±1.3 amol/µg total RNA) than ventricle (0.6±0.1 amol/µg, P<0.05), whereas TWIK-1 mRNA was more concentrated in ventricle (18.1±4.3 amol/µg) than atrium (1.4±0.3 amol/µg, P<0.05). Concentrations of hIRK (42.7±6.7 amol/µg in atrium vs 57.1±9.2 amol/µg in ventricle) and HH-IRK1 (2.0±0.5 amol/µg in atrium vs 1.5±0.5 amol/µg in ventricle) were comparable. No significant differences in IRK subunit transcript concentrations were found between normal and failing ventricles.
Conclusions—mRNAs for all 4 IRKs are detected in human atrium and ventricle, but the mRNA copy number of a low-conductance subunit (HIR) is larger in atrium and the copy number of a weakly rectifying subunit (TWIK-1) is larger in ventricle. These differences in relative message levels may provide a potential molecular basis for different properties of IK1 in human atrium compared with ventricle.
Key Words: atrium • ventricles • heart failure • potassium • RNA
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The inward rectifier potassium current IK1 plays a critical role in determining membrane resting potential and contributing to the final phase of action potential repolarization in cardiac cells. Four different cDNA clones belonging to the IRK (inward rectifier K+ channel) family have been detected in the human heart: HH-IRK1,1 2 3 hIRK,4 HIR,5 6 7 and TWIK18 (Table 1
). Expression of each in
heterologous systems gives rise to currents qualitatively similar to
native IK1,1 2 3 4 5 6 7 8 although
functional differences exist. Evidence has accumulated that
endogenous IK1 may actually be
composed of a number of distinct channel
populations.9 10 11 12 13 14
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Important differences of IK1 exist between atrium and ventricle.14 15 16 17 18 Atrial IK1 has a smaller conductance, current density, and channel open times compared with ventricular IK1. It is possible that differences between atrial and ventricular IK1 are due to differences in concentrations of various IRK clones. It is further conceivable that differences in IK1 between normal and failing ventricles19 20 may be due to varying IRK subunit distribution.
The present study was designed to quantify mRNA levels of IRK clones in normal human atrium and in normal and failing human ventricle. We particularly sought to determine whether there are differences in IRK mRNA expression profiles between atrium and ventricle that could be related to some of the differences in their IK1 properties.
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Methods |
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Tissue Handling
Normal atrial appendages (
0.3 g each) were obtained from 15
patients undergoing coronary bypass surgery. Diseased
ventricular tissues (1 g each) were dissected from the
left ventricle of explanted hearts from 6 patients undergoing heart
transplantation. Two had myocarditis, 2 idiopathic
cardiomyopathy, 1 aortic valve disease, and 1
ischemic cardiomyopathy. Healthy
ventricular preparations (5 mg) were obtained by
endocardial biopsy in follow-up after heart transplantation. Samples (2
per patient) were obtained from 14 patients free of rejection (disease
before transplantation: ischemic
cardiomyopathy [6], idiopathic
cardiomyopathy [6], myocarditis [2]). Atrial
samples were quickly frozen in liquid nitrogen and stored at -80°C.
Ventricular tissues were immediately immersed into Trizol
solution and processed for RNA isolation.
Patch-Clamp Recording
The procedure for isolating human cardiac cells has been
described previously in detail.21 When cell yield
was optimal the cells were suspended in a storage solution (in
mmol/L, KCl 20, KH2PO4 10,
K glutamate 70, EGTA 5, glucose 10, taurine 10, albumin 0.1%,
pH 7.3, with KOH).
Ca2+-tolerant, quiescent rod-shaped cells with
tight gigaseals were used for data analysis. Borosilicate glass
microelectrodes (1 mm optical density) had tip resistance of 1 to
2 M
when filled with (mmol/L): KCl 20, K aspartate 120,
MgCl2 1, HEPES 5, EGTA 5,
Na2-ATP 4, K-ATP 5, pH 7.3, with KOH. Cells were
superfused with Tyrode solution at 37°C containing (mmol/L): NaCl
137, KCl 5.4, CaCl2 1,
MgCl2 0.8, HEPES 10, glucose 10,
CaCl2 0.2, 4-aminopyridine 1,
glyburide 0.01, and atropine 0.001. The electrodes were connected to an
Axopatch 1-D amplifier (Axon Instruments). Command pulses were
generated with pCLAMP6 software. After gigaseal formation (seal
resistance >10 G), suction was applied to rupture the membrane for
whole-cell recording. Series resistance and system capacitance
were compensated.
RNA Purification
Tissue specimens were homogenized in Trizol reagent
(Gibco BRL). Total RNA was extracted by the acidic guanidinium
isothiocyanate method with chloroform and isopropanol precipitation and
incubated with DNase I (0.1 U/µL) at 37°C for 15 minutes. Genomic
DNA was removed by phenol/chloroform extraction. Isolated RNA was
quantified (spectrophotometric absorbance at 260 nm) and purity was
confirmed by the A260/A280
ratio. Integrity of total RNA was evaluated by ethidium bromide
staining in denaturing agarose gels. RNA samples were stored in
DEPC-treated, double-distilled H2O at
-80°C.
Construction of RNA Mimics (Internal Standards)
Primers
Primers were designed to avoid secondary and complementary
structures. Gene-specific primer (GSP) pairs were designed on the basis
of published cDNA sequences from regions with minimal homology among
IRKs and specificity verified by comparison with the GenBank database
with the use of BLAST and FASTA. The process for synthesis of the RNA
mimic and reverse transcription–polymerase chain reaction (RT-PCR) is
illustrated in Figure 1. Chimeric primer
pairs (Table 2) were constructed with
sequences homologous to human cardiac 
-actin cDNA flanked at the 5'
ends by IRK GSPs and an 8-nucleotide (GGCCGCGG) linker
homologous to 3' end sequence of T7 promoter was conjugated to the 5'
end of each forward chimeric primer.
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Synthesis of RNA Mimic
First-strand cDNA was synthesized by RT with mRNA extracted from
human ventricular tissues and was used as a template for
PCR amplification with chimeric primer pairs to obtain a cDNA mimic
consisting of a 460-bp fragment of human cardiac -actin flanked by
an IRK GSP sense sequence at the 5' end and an antisense sequence at
the 3' end. A second run of PCR was performed with the T7 promoter
sequence as a forward primer and a reverse IRK GSP. The resulting
products were cDNA fragments carrying a T7 promoter followed by a
forward IRK GSP, an -actin fragment and then a reverse IRK GSP. The
products were then gel-purified with the Glassmax DNA Isolation
Spin Cartridge System (Gibco BRL). RNA internal standards (mimics) were
generated by in vitro transcription with purified cDNA mimics as
templates (mMESSAGE mMACHINE kit, Ambion). To remove
remaining cDNA templates, the reaction products were incubated with
RNAse-free DNase I (37°C, 30 minutes) followed by phenol/chloroform
extraction and isopropanol precipitation. The uniqueness of RNA mimics
was confirmed by the presence of single bands of expected size on a
denaturing gel. The synthetic RNA mimics thus had GSPs for the target
IRK mRNA at both ends and a 460-bp fragment of human cardiac -actin
in the middle.
Competitive RT-PCR
Reverse Transcription
RNA mimic samples with serial 10-fold dilutions were prepared
and added to 1 µg of sample RNA. RNAs were denatured at 65°C for 15
minutes. RT was conducted in a 20-µL reaction mixture containing 1x
reaction buffer (10 mmol/L Tris-HCl [pH 8.3], 50 mmol/L
KCl, 2.5 mmol/L MgCl2, 1 mmol/L dNTPs
(Boehringer Mannheim), 3.2 µg random primers
p(dN)6 (Boehringer Mannheim), 5
mmol/L DTT, 50 U RNase inhibitor (Gibco BRL), and 200 U
M-MLV RT (Gibco RBL). First-strand cDNAs were synthesized at 42°C for
60 minutes and the remaining enzymes inactivated at 99°C
for 5 minutes.
PCR Amplification
First-strand cDNA (10 µL) was used as an amplification
template in a 50-µL reaction mixture. Reagents in each reaction
included 10 mmol/L Tris-HCl (pH 8.3), 50 mmol/L KCl, 1.5
mmol/L MgCl2, 1 mmol/L dNTPs, 0.5
µmol/L of each GSP pair, and 2.5 U of Taq polymerase (Gibco BRL).
Reactions were hot-started at 94°C and continued for 3 minutes of
initial melting. The cycling profiles were 30 seconds of denaturing
(94°C), 30 seconds of annealing (54°C), and 40 seconds of extension
(72°C) for 30 cycles, followed by a final extension step (5 minutes
at 72°C).
Quantification of PCR Products
Densitometry was used for quantification of PCR
products.22 PCR products were visualized
under UV light with ethidium bromide staining in 1.5% agarose gel.
Ethidium bromide fluorescence images were captured by a
Nighthawk camera under UV light and band density determined with
Quantity One software. A DNA mass marker (100 ng) was used to
analyze the size and quantity of PCR products. The density
of the DNA mass ladder was used to generate a standard curve by linear
regression with extrapolation to zero for each experiment. The density
of each sample band was then converted to an absolute quantity by
calibrating to the standard curve.
Control Experiments
To ensure the equality of RNA input, additional experiments were
performed to PCR-amplify human cardiac -actin from each sample.
Equal amplification from different RNA samples makes it unlikely that
observed differences are due to biased input of initial amount of total
RNA (Figure 2). Equal efficiency of PCR
amplification for sample RNA and RNA mimic was verified by quantitative
analyses of PCR products for each construct coamplified in
a single reaction tube, as illustrated in Figure 3.
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Data Analysis
Data are expressed as mean±SEM. Each determination for a given
mRNA concentration was performed on a sample from an individual heart,
for example, numbers of determinations given are for separate hearts.
Statistical comparisons were performed with unpaired Student's
t tests. A 2-tailed probability <0.05 was taken to indicate
statistical significance.
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Results |
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Comparisons of IK1 in Human Atrial and Ventricular Cells
Figure 4
shows examples of
IK1 recorded from human atrial (Figure 4A)
and ventricular (Figure 4B) cells.
IK1 is smaller in atrium than in ventricle.
Atrial cells showed very little outward current at voltages positive to
the reversal potential, whereas ventricular myocytes
carried significant outward currents between -80 and 0 mV. Figure 4C
shows mean current density-voltage relations for 5 atrial and 6
ventricular myocytes. IK1 currents
are shown relative to maximum current (at -100 mV) in Figure 4D.
Despite this control for differences in maximum density between atrial
and ventricular IK1, atrial cells
carry much less outward current.
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Comparisons of IRK Transcriptional Profiles in Human Atrium
and Ventricle
Figure 5 shows
representative gels of competitive RT-PCR products.
The upper bands represent products from RNA internal
standards, and the lower bands are target gene sequences coamplified in
the same RT-PCR reactions. As the RNA internal standard concentration
in the initial reaction mixture decreased, the target gene signals
became stronger. The TWIK-1 internal standard bands are comparable for
atrium and ventricle, but the target gene bands are more intense in
ventricular tissue. The point of equivalence (where the
density of bands are comparable) for TWIK-1 occurs at the fourth lane
in atrium but at approximately the third lane in ventricle, indicating
an 10-fold greater concentration in ventricle.
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For HIR, the target gene bands are stronger in atrium than in
ventricle. The point of equivalence is in the third lane for atrium and
the fourth lane for ventricle. Thus the HIR mRNA concentration is an
order of magnitude higher in atrium. In contrast to TWIK-1 and HIR, the
gels for hIRK and HH-IRK1 are quite similar in both tissues. Gels of
the type shown in Figure 5
were used to quantify target gene mRNA
concentrations as illustrated in Figure 6. The relation between log (target over
mimic intensity ratio) and log (mimic concentration) was well fitted by
linear regression. The horizontal axis intercept (corresponding to a
concentration ratio of 1) indicates the point at which target gene mRNA
concentration equals that of the internal standard. The mean mRNA
expression level of TWIK-1 was approximately 13 times higher in
ventricle (18.1±4.3 amol/µg RNA, n=11) than in atrium (1.4±0.3
amol/µg RNA, n=8, P<0.05). HIR transcripts were 12-fold
more abundant in atrium (7.1±1.3 amol/µg RNA, n=9) compared with
ventricle (0.6±0.1 amol/µg RNA, n=7, P<0.05). Atrial and
ventricular concentrations of hIRK and HH-IRK1 were
similar.
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The highest mRNA concentrations in both atrium and ventricle were for hIRK. TWIK-1 mRNA was abundant in ventricle, but its concentration was lower than that of any other clone in atrium. HIR concentrations were relatively high in atrium and very low in ventricle. Expression of HH-IRK1 mRNA was relatively weak in both atrium and ventricle.
Comparisons of IRK Transcription Profiles in Healthy and Diseased
Human Ventricles
Comparisons of mRNA levels in ventricular
tissues from nonfailing and failing hearts are illustrated in Figure 7. There were no
statistically-significant differences in mRNA concentrations between
normal and failing ventricle for any of the clones.
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Evaluation of Possible Contamination of Sample RNA by
Noncardiac Tissue
Previous investigators have assayed mRNA for the neuronal
acetylcholine ß4 subunit to exclude neural
contamination of cardiac mRNA measurements.23 We
used published sequences of the human nicotinic receptor
ß4 subunit24 to design
primer pairs for RT-PCR. Figure 8A shows
representative ethidium bromide-stained PCR
products in an agarose gel. ß4 subunit mRNA
was consistently detected in 3 samples from rat brain but was
absent in all 9 atrial and 17 ventricular samples.
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Contamination by vascular tissue was excluded by RT-PCR
amplification of the maxi-K channel. Total RNA isolated from rat
vascular smooth muscle, in which maxi-K channels carry a substantial
current, was used as a positive control. PCR primer pairs were designed
on the basis of published sequences.25 Figure 8B
shows the strong maxi-K channel signal typical of vascular preparations
(lane 1) and the absence of a corresponding band in heart tissue (lanes
2 to 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this article, we report the results of an analysis of the relative abundance of mRNA of 4 IRK clones in human atrium and ventricle. We found measurable concentrations of all clones and significant expression profile differences between normal atrium and ventricle.
Biophysical Differences Among Cloned IRK Channels
The 4 different IRK cDNA clones isolated from the human share have
distinct biophysical characteristics. A distinguishing feature of
TWIK-1 is its weak inward rectification.8 26
Unlike other IRKs, which begin to rectify at potentials positive to
-50 mV ([K+]o5
mmol/L), TWIK-1 begins to rectify at 0 mV. Consequently, TWIK-1 carries
significant outward currents between -60 and 0 mV. HIR is
distinguished by its relatively small single-channel conductance (10
pS under symmetrical K+
conditions),5 6 much less than the other IRKs
hIRK (36 pS),4 TWIK-1 (34
pS),8 and HH-IRK1 (30 to 49
pS).1 2 3
Potential Role of Differential IRK Abundance in Native
IK1 Heterogeneity
IK1 has been studied in many species,
including rat,9 guinea
pig,14 rabbit,15 and
human.16 17 18 A common observation is that atrial
IK1 has a smaller outward current carrying
capacity and a smaller current density. Differences in
IK1 are believed to be important in contributing
to characteristic differences between atrial and
ventricular action potentials, particularly the less
negative resting potential and slower terminal repolarization typical
of atrial cells. We found that the mRNA concentration of TWIK-1 is 13
times higher in ventricle then in atrium. Because TWIK-1 shows less
rectification than the other IRK clones,8 26 it
is possible that its relative absence in atrium accounts for the small
outward current of atrial IK1; however, distinct
currents typical of TWIK-1 were not detected. HIR transcripts were 12
times more abundant in atrium versus ventricle. The single-channel
conductance of HIR is approximately one third less than that of other
IRKs,5 6 raising the possibility that the greater
preponderance of HIR contributes to the smaller macroscopic
IK1 conductance in atrium.
Native IK1 has been found to show considerable complexity at the single-channel level.4 9 11 Wible et al4 demonstrated the presence of four discrete IK1 channels in human heart tissue. A 21-pS channel was seen in 77% of patches, a 35-pS channel in 60% of patches, a 41-pS channel in 36%, and a 9-pS channel in only 4%. Although these conductances most resembled those of HH-IRK1, TWIK-1, hIRK, and HIR, respectively, none of the native channels were identical to any of the heterologously-expressed cloned channels.4 In 2 other studies in human atrial cells, only 27-pS channels were described, but open times differed substantially.18 27 Our experiments provide evidence for the presence of four different IRKs in both human atrium and ventricle, with distinct differences between atrium and ventricle; however, functional heterogeneity may be produced not only by differences in IRK species but also by heteromultimer formation. Further studies of cardiac IRK protein expression and coassembly are warranted.
IRK Levels in Failing Ventricle
The only other publication on ion channel mRNA concentrations in
the failing human ventricle that we were able to identify found that
the level of mRNA encoding the DHP receptor was decreased by 47% in
patients with heart failure compared with normal control subjects and
the number of DHP binding sites was decreased by 35% to
48%.28 A study in abstract form compared levels
of various K+ channel mRNA, including
IK1 (IRK clone not specified), in normal and
failing human hearts.29 In agreement with our
findings, message levels for IK1 were not altered
in failing hearts. Because IRK mRNA concentrations do not appear to
decrease in the failing ventricle, posttranscriptional factors may be
important in decreasing IK1 density.
Potential Limitations
Changes in steady-state levels of mRNA often parallel alterations
in protein production and provide insights into underlying
molecular mechanisms. For example, Levitan et
al30 reported parallel inhibition by
depolarization of Kv 1.5 voltage-gated K+ channel
gene transcription and protein expression in pituitary cells. Parallel
changes in Kv 2.1 and Kv 4.2 mRNA levels and protein expression were
also found in rat ventricles after experimental myocardial
infarction.31 On the other hand, there are
well-demonstrated instances of a lack of correlation between mRNA and
protein expression. For example, although Kv 1.4 mRNA is present in
rat cardiac cells, no proteins corresponding to Kv 1.4 could be found
in the membrane.32 The inward rectification of
IK1 is the consequence of voltage-dependent
blockade by Mg2+ and polyamines, and the
differences in the rectification between atrium and ventricle could be
due to different block of IK1 by
Mg2+ and polyamines in the 2 tissue
types.33 34 Thus although the differences in IRK
mRNA expression that we found may be important in contributing to
differences between atrial and ventricular
IK1, they are unlikely to be the only factors
involved and further research is necessary to evaluate other potential
components.
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Acknowledgments |
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This work was supported by the Medical Research Council of Canada, the Heart and Stroke Foundation of Quebec, the Fonds de Recherche de l'Institut de Cardiologie de Montréal, and an Establishment Grant from the Fonds de Recherche en Santé du Québec (Dr Wang), a Research scholarship of the Heart and Stroke Foundation of Canada (Dr Wang), and a studentship award from the Heart and Stroke Foundation of Canada (Lixia Yue). The authors thank XiaoFan Yang for excellent technical assistance and Caroll Boyer for secretarial help.
Received April 1, 1998; revision received July 24, 1998; accepted August 13, 1998.
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 A. A. Rodriguez-Menchaca, R. A. Navarro-Polanco, T. Ferrer-Villada, J. Rupp, F. B. Sachse, M. Tristani-Firouzi, and J. A. Sanchez-Chapula The molecular basis of chloroquine block of the inward rectifier Kir2.1 channel PNAS, January 29, 2008; 105(4): 1364 - 1368. [Abstract] [Full Text] [PDF]
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E. Saygili, O. R. Rana, E. Saygili, H. Reuter, K. Frank, R. H. G. Schwinger, J. Muller-Ehmsen, and C. Zobel Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal myocytes Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2898 - H2905. [Abstract] [Full Text] [PDF]
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 S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
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R. R. Smith, L. Barile, H. C. Cho, M. K. Leppo, J. M. Hare, E. Messina, A. Giacomello, M. R. Abraham, and E. Marban Regenerative Potential of Cardiosphere-Derived Cells Expanded From Percutaneous Endomyocardial Biopsy Specimens Circulation, February 20, 2007; 115(7): 896 - 908. [Abstract] [Full Text] [PDF]
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J. Fauconnier, A. Lacampagne, J.-M. Rauzier, G. Vassort, and S. Richard Ca2+-dependent reduction of IK1 in rat ventricular cells: A novel paradigm for arrhythmia in heart failure? Cardiovasc Res, November 1, 2005; 68(2): 204 - 212. [Abstract] [Full Text] [PDF]
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 Y. Fang, G. Schram, V. G. Romanenko, C. Shi, L. Conti, C. A. Vandenberg, P. F. Davies, S. Nattel, and I. Levitan Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2 Am J Physiol Cell Physiol, November 1, 2005; 289(5): C1134 - C1144. [Abstract] [Full Text] [PDF]
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J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]
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L. Zhang, D. W. Benson, M. Tristani-Firouzi, L. J. Ptacek, R. Tawil, P. J. Schwartz, A. L. George, M. Horie, G. Andelfinger, G. L. Snow, et al. Electrocardiographic Features in Andersen-Tawil Syndrome Patients With KCNJ2 Mutations: Characteristic T-U-Wave Patterns Predict the KCNJ2 Genotype Circulation, May 31, 2005; 111(21): 2720 - 2726. [Abstract] [Full Text] [PDF]
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 D.-H. Yan, K. Nishimura, K. Yoshida, K. Nakahira, T. Ehara, K. Igarashi, and K. Ishihara Different intracellular polyamine concentrations underlie the difference in the inward rectifier K+ currents in atria and ventricles of the guinea-pig heart J. Physiol., March 15, 2005; 563(3): 713 - 724. [Abstract] [Full Text] [PDF]
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K. Zorn-Pauly, P. Schaffer, B. Pelzmann, P. Lang, H. Machler, B. Rigler, and B. Koidl If in left human atrium: a potential contributor to atrial ectopy Cardiovasc Res, November 1, 2004; 64(2): 250 - 259. [Abstract] [Full Text] [PDF]
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G. F. Tomaselli and D. P. Zipes What Causes Sudden Death in Heart Failure? Circ. Res., October 15, 2004; 95(8): 754 - 763. [Abstract] [Full Text] [PDF]
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A. S. Dhamoon, S. V. Pandit, F. Sarmast, K. R. Parisian, P. Guha, Y. Li, S. Bagwe, S. M. Taffet, and J. M.B. Anumonwo Unique Kir2.x Properties Determine Regional and Species Differences in the Cardiac Inward Rectifier K+ Current Circ. Res., May 28, 2004; 94(10): 1332 - 1339. [Abstract] [Full Text] [PDF]
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J. F. Heubach, E. M. Graf, J. Leutheuser, M. Bock, B. Balana, I. Zahanich, T. Christ, S. Boxberger, E. Wettwer, and U. Ravens Electrophysiological properties of human mesenchymal stem cells J. Physiol., February 1, 2004; 554(3): 659 - 672. [Abstract] [Full Text] [PDF]
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S. Zicha, I. Moss, B. Allen, A. Varro, J. Papp, R. Dumaine, C. Antzelevich, and S. Nattel Molecular basis of species-specific expression of repolarizing K+ currents in the heart Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1641 - H1649. [Abstract] [Full Text] [PDF]
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G. Schram, M. Pourrier, Z. Wang, M. White, and S. Nattel Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents Cardiovasc Res, August 1, 2003; 59(2): 328 - 338. [Abstract] [Full Text] [PDF]
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C. Zobel, H. C. Cho, T.-T. Nguyen, R. Pekhletski, R. J Diaz, G. J Wilson, and P. H Backx Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2 J. Physiol., July 15, 2003; 550(2): 365 - 372. [Abstract] [Full Text] [PDF]
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 X.-S. Zhao, T. D. Gallardo, L. Lin, J. J. Schageman, and R. V. Shohet Transcriptional mapping and genomic analysis of the cardiac atria and ventricles Physiol Genomics, December 26, 2002; 12(1): 53 - 60. [Abstract] [Full Text] [PDF]
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W. Han, L. Zhang, G. Schram, and S. Nattel Properties of potassium currents in Purkinje cells of failing human hearts Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2495 - H2503. [Abstract] [Full Text] [PDF]
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G. Schram, P. Melnyk, M. Pourrier, Z. Wang, and S. Nattel Kir2.4 and Kir2.1 K+ channel subunits co-assemble: a potential new contributor to inward rectifier current heterogeneity J. Physiol., October 15, 2002; 544(2): 337 - 349. [Abstract] [Full Text] [PDF]
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 A. Collins and M. Larson Differential Sensitivity of Inward Rectifier K+ Channels to Metabolic Inhibitors J. Biol. Chem., September 20, 2002; 277(39): 35815 - 35818. [Abstract] [Full Text] [PDF]
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C. A. Karle, E. Zitron, W. Zhang, G. Wendt-Nordahl, S. Kathofer, D. Thomas, B. Gut, E. Scholz, C.-F. Vahl, H. A. Katus, et al. Human Cardiac Inwardly-Rectifying K+ Channel Kir2.1b Is Inhibited by Direct Protein Kinase C-Dependent Regulation in Human Isolated Cardiomyocytes and in an Expression System Circulation, September 17, 2002; 106(12): 1493 - 1499. [Abstract] [Full Text] [PDF]
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P. Melnyk, L. Zhang, A. Shrier, and S. Nattel Differential distribution of Kir2.1 and Kir2.3 subunits in canine atrium and ventricle Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1123 - H1133. [Abstract] [Full Text] [PDF]
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K. Komukai, F. Brette, and C. H. Orchard Electrophysiological response of rat atrial myocytes to acidosis Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H715 - H724. [Abstract] [Full Text] [PDF]
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R. Preisig-Muller, G. Schlichthorl, T. Goerge, S. Heinen, A. Bruggemann, S. Rajan, C. Derst, R. W. Veh, and J. Daut Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome PNAS, May 28, 2002; 99(11): 7774 - 7779. [Abstract] [Full Text] [PDF]
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G. Schram, M. Pourrier, P. Melnyk, and S. Nattel Differential Distribution of Cardiac Ion Channel Expression as a Basis for Regional Specialization in Electrical Function Circ. Res., May 17, 2002; 90(9): 939 - 950. [Abstract] [Full Text] [PDF]
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D. Dobrev, E. Graf, E. Wettwer, H. M. Himmel, O. Hala, C. Doerfel, T. Christ, S. Schuler, and U. Ravens Molecular Basis of Downregulation of G-Protein-Coupled Inward Rectifying K+ Current (IK,ACh) in Chronic Human Atrial Fibrillation: Decrease in GIRK4 mRNA Correlates With Reduced IK,ACh and Muscarinic Receptor-Mediated Shortening of Action Potentials Circulation, November 20, 2001; 104(21): 2551 - 2557. [Abstract] [Full Text] [PDF]
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H. Wang, H. Han, L. Zhang, H. Shi, G. Schram, S. Nattel, and Z. Wang Expression of Multiple Subtypes of Muscarinic Receptors and Cellular Distribution in the Human Heart Mol. Pharmacol., April 16, 2001; 59(5): 1029 - 1036. [Abstract] [Full Text]
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G. Xin Liu, C. Derst, G. Schlichthorl, S. Heinen, G. Seebohm, A. Bruggemann, W. Kummer, R. W Veh, J. Daut, and R. Preisig-Muller Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes J. Physiol., April 1, 2001; 532(1): 115 - 126. [Abstract] [Full Text] [PDF]
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D. Dobrev, E. Wettwer, H. M. Himmel, A. Kortner, E. Kuhlisch, S. Schuler, W. Siffert, and U. Ravens G-Protein {beta}3-Subunit 825T Allele Is Associated With Enhanced Human Atrial Inward Rectifier Potassium Currents Circulation, August 8, 2000; 102(6): 692 - 697. [Abstract] [Full Text] [PDF]
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H. Shi, H.-Z. Wang, and Z. Wang Extracellular Ba2+ blocks the cardiac transient outward K+ current Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H295 - H299. [Abstract] [Full Text] [PDF]
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P. Schaffer, B. Pelzmann, E. Bernhart, P. Lang, H. Machler, B. Rigler, and B. Koidl Repolarizing currents in ventricular myocytes from young patients with tetralogy of Fallot Cardiovasc Res, August 1, 1999; 43(2): 332 - 343. [Abstract] [Full Text] [PDF]
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H. Shi, H. Wang, and Z. Wang Identification and Characterization of Multiple Subtypes of Muscarinic Acetylcholine Receptors and Their Physiological Functions in Canine Hearts Mol. Pharmacol., March 1, 1999; 55(3): 497 - 507. [Abstract] [Full Text]
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H. Wang, B. Yang, Y. Zhang, H. Han, J. Wang, H. Shi, and Z. Wang Different Subtypes of alpha 1-Adrenoceptor Modulate Different K+ Currents via Different Signaling Pathways in Canine Ventricular Myocytes J. Biol. Chem., October 26, 2001; 276(44): 40811 - 40816. [Abstract] [Full Text] [PDF]
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