This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brahmajothi, M. V. Articles by Strauss, H. C. Search for Related Content PubMed PubMed Citation Articles by Brahmajothi, M. V. Articles by Strauss, H. C.

(Circulation Research. 1996;78:1083-1089.)
© 1996 American Heart Association, Inc.

Articles

In Situ Hybridization Reveals Extensive Diversity of K⁺ Channel mRNA in Isolated Ferret Cardiac Myocytes

Mulugu V. Brahmajothi, Michael J. Morales, Shuguang Liu, Randall L. Rasmusson, Donald L. Campbell, Harold C. Strauss

From the Departments of Pharmacology (M.V.B., M.J.M., D.L.C., H.C.S.) and Medicine (S.L., H.C.S.), Duke University Medical Center, and the Department of Biomedical Engineering (R.L.R.), School of Engineering, Duke University, Durham, NC.

Correspondence to Michael J. Morales, Department of Pharmacology Box 3845, Bell Building, Room 345, Duke University Medical Center, Durham, NC 27710. Internet mmorales@acpub.duke.edu.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Abstract The molecular basis of K⁺ currents that generate repolarization in the heart is uncertain. In part, this reflects the similar functional properties different K⁺ channel clones display when heterologously expressed, in addition to the molecular diversity of the voltage-gated K⁺ channel family. To determine the identity, regional distribution, and cellular distribution of voltage-sensitive K⁺ channel mRNA subunits expressed in ferret heart, we used fluorescent labeled oligonucleotide probes to perform in situ hybridization studies on enzymatically isolated myocytes from the sinoatrial (SA) node, right and left atria, right and left ventricles, and interatrial and interventricular septa. The most widely distributed K⁺ channel transcripts in the ferret heart were Kv1.5 (present in 69.3% to 85.6% of myocytes tested, depending on the anatomic region from which myocytes were isolated) and Kv1.4 (46.1% to 93.7%), followed by Kv1.2, Kv2.1, and Kv4.2. Surprisingly, many myocytes contain transcripts for Kv1.3, Kv2.2, Kv4.1, Kv5.1, and members of the Kv3 family. Kv1.1, Kv1.6, and Kv6.1, which were rarely expressed in working myocytes, were more commonly expressed in SA nodal cells. IRK was expressed in ventricular (84.3% to 92.8%) and atrial (52.4% to 64.0%) cells but was nearly absent (6.6%) in SA nodal cells; minK was most frequently expressed in SA nodal cells (33.7%) as opposed to working myocytes (10.3% to 29.3%). Two gene products implicated in long-QT syndrome, ERG and KvLQT1, were common in all anatomic regions (41.1% to 58.2% and 52.1% to 71.8%, respectively). These results show that the diversity of K⁺ channel mRNA in heart is greater than previously suspected and that the molecular basis of K⁺ channels may vary from cell to cell within distinct regions of the heart and also between major anatomic regions.

Key Words: K⁺ channel • heart • gene expression • localization • SA node

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Atrial tachyarrhythmias are an important cause of morbidity in patients with heart disease. The mechanisms underlying these arrhythmias and their sites of origin or reentrant paths vary substantially.^{1 2 3 4 5} Although pharmacotherapy with Na⁺ and K⁺ channel blockers can be effective against many different atrial arrhythmias, shortcomings resulting from toxicity and limited efficacy underscore the current limitations in antiarrhythmic therapy.⁶ Since many current antiarrhythmic agents are primarily targeted at refractoriness and/or repolarization, these shortcomings ultimately reflect our limited understanding of the molecular basis of the K⁺ currents generating repolarization.

Until recently, the K⁺ currents that dominate atrial repolarization were thought to be the transient outward current (I_to)⁷ and two delayed rectifier currents: a rapidly activating inwardly rectifying current (I_Kr) and a slower activating current (I_Ks).^{8 9 10 11 12 13} However, other K⁺ currents could potentially contribute to repolarization, eg, the ultrarapidly activating current (I_Kur).^{14 15} Despite extensive physiological characterization, the molecular basis of each of these currents is still debated. Assignment of currents to specific channel cDNAs is complicated by their similar functional properties and the wide molecular diversity of the voltage-gated K⁺ channel family.¹⁶ An additional confounding factor is the difference between functional properties of native human cardiac myocyte K⁺ currents versus those from other mammalian species (rabbit, dogs, rats, and guinea pigs). Recent analyses of the functional properties of the different K⁺ currents in ferret ventricular myocytes demonstrate that the phenotypes of ferret K⁺ currents closely resemble those of human ventricular myocytes,^{7 17 18 19} suggesting that the ferret is a particularly appropriate animal model in which to study mammalian cardiac K⁺ currents.

Originally discovered in Drosophila, the evolutionarily conserved Shaker family of K⁺ channels consists of six distinct subclasses: Shaker (Kv1), Shab (Kv2), Shaw (Kv3), Shal (Kv4), Kv5, and Kv6. Four of these (Kv1 through Kv4) have several mammalian homologues, whereas Kv5 and Kv6 each have only one known member.¹⁶ Although K⁺ channels in the Kv1 through Kv4 families have received the most experimental attention, additional attention will undoubtedly be focused on two channels implicated in familial forms of long-QT syndrome.^{20 21} One of these channels, ERG, is a member of the ether-à-go-go family,²² which are structurally similar to Shaker-type channels. Heterologously expressed ERG produces currents similar to that of the cardiac I_Kr.^{23 24} The other, KvLQT1, is a physiologically uncharacterized channel that represents a new class of the Shaker family.²¹

Two K⁺ channel families that lack the six membrane-spanning domains of the Shaker-type channels probably play a role in the generation of cardiac K⁺ currents. The IRK family of inwardly rectifying K⁺ channels has a structure with only two membrane-spanning domains on either side of a pore structure conserved with other members of the Shaker superfamily.²⁵ The minK channels have a structure completely unrelated to other channels, with only one membrane-spanning segment.²⁶ Heterologous expression of this protein results in a slowly activating delayed rectifier current.^{27 28}

To identify K⁺ channels expressed in heart, Dixon and McKinnon²⁹ used an RNase protection assay to detect the expression of 15 different K⁺ channels in rat atrial and ventricular muscle. Of these, Kv1.2, Kv1.4, Kv1.5, Kv2.1, and Kv4.2 were expressed at relatively high levels. The abundance of the remaining mRNAs ranged from low to undetectable. Any attempt to draw conclusions about transcript expression in heart cells using this method is predicated on the assumption that the tissue samples used consisted solely of myocardial cells and that expression was uniform between cells. However, it is widely recognized that only 70% of the cells isolated from heart consist of cardiac myocytes.³⁰ In addition, some genes of interest were not included in this analysis.

To further our understanding of the molecular basis of cardiac K⁺ currents, we set out to determine the following: (1) the identity of voltage-sensitive K⁺ channel mRNAs expressed in cardiac myocytes, (2) the differences in voltage-gated K⁺ channel expression between major anatomic regions of the heart (ie, left and right atria, left and right ventricles, sinoatrial [SA] node, and ventricular and atrial septa), and (3) the uniformity of gene expression between myocardial cells in major anatomic regions of the heart. The present study used in situ hybridization on large numbers of enzymatically isolated single myocytes obtained from the major anatomic regions of the ferret heart, ensuring that our sample population was essentially free of contamination by nonmyocyte cell types.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Cell Preparation
Single cardiac myocytes were isolated from the hearts of male ferrets (10 to 20 weeks old) using a Langendorff perfusion technique as previously described.³¹ After 25 to 40 minutes of perfusion with proteolytic enzymes, the heart was removed from the Langendorff apparatus, and the left ventricle, right ventricle, ventricular septum, left atrium, right atrium, atrial septum, and SA node were dissected free. Each dissected region was then placed in a separate 15-mL conical tissue culture tube containing fresh proteolytic enzyme solution to which an additional 10 mg/mL of BSA (essentially fatty acid free, Sigma Chemical Co) was added. The tubes were then gently shaken (0.5 to 1 cycle per second) on a rocker table at 37°C. Aliquots of myocytes were collected at 10- to 15-minute intervals, gently centrifuged, and the pellets were directly resuspended in normal 1.8 mmol/L Ca²⁺–containing control saline. After isolation, the myocytes were fixed for 30 minutes in 3% paraformaldehyde, subsequently washed twice with PBS, and then used directly for in situ hybridization.

Preparation of Probe and Labeling
K⁺ channel subunit sequences from both the GenBank library and our previous cloning studies in ferret heart were used to design oligonucleotide probes of 45 to 50 nucleotides (see Table 1). Where possible, ferret or human sequences were used. When computer analysis (Gene Runner v3.0, Hastings Software) predicted extensive secondary structure, inosines were used to disrupt the potential structure. The uniqueness of the probes was confirmed by comparison with the entire GenBank database using BLAST³² and FASTA³³ and by direct comparison with known channel sequences. A probe was judged to be suitable if (1) no other channel appeared in the top 50 matches of the BLAST or the FASTA search and (2) the individual searches of the antisense probe of related channel sequences showed no more similarity than the corresponding sense probe. The sequence of the probes, location in the GenBank entry, and the family from which they are derived are presented in Table 1. It was not possible to design unique probes to members of the IRK family; the IRK probe³⁴ has 67% sequence identity with rat B-IRK2³⁵ and may cross-react with other unknown members of that family. Oligonucleotides were synthesized and gel-purified by Genosys Inc. The oligonucleotide probes were 3' end-labeled with digoxigenin-ddUTP using terminal transferase as described by the manufacturer's protocol (Boehringer-Mannheim).

View this table: [in this window] [in a new window]   Table 1. Probes Used for In Situ Hybridization

In Situ Hybridization
In situ hybridization was performed by a modification of established techniques.³⁶ The cells were suspended in 0.1 mol/L triethanolamine-OH, pH 7.2, 0.15 mol/L NaCl (tetraethylammonium buffer), incubated for 3 minutes at 37°C, treated with acetic anhydride (0.25% in tetraethylammonium buffer) for 10 minutes at 37°C (to inactivate residual protease), washed in PBS for 5 minutes at 37°C, and incubated in 2x SSC (1x SSC contains 150 mmol/L NaCl and 15 mmol/L Na₃ citrate, pH 7.0) for 10 minutes at room temperature. The cells were prehybridized with 50% deionized formamide, 4x SSC, 1x Denhardt's solution, 0.5 mg/mL salmon sperm DNA, 0.5 mg/mL yeast tRNA, and 10% dextran sulfate for 30 minutes at room temperature. The digoxigenin-labeled probe (100 ng/mL) was added and incubated overnight at 42°C. The samples were washed with 4x SSC for 10 minutes at room temperature, 1x SSC for 10 minutes at room temperature, 0.1x SSC at 42°C for 30 minutes, and 0.1x SSC for 10 minutes at room temperature. Cells were then washed in 100 mmol/L Tris-HCl plus 150 mmol/L NaCl (pH 7.5) and incubated for 30 minutes in the same buffer containing 2% normal sheep serum and 0.3% Triton X-100. The cells were then incubated with fluorescein isothiocyanate–conjugated anti-digoxigenin antibody (1:500 dilution in blocking buffer, Boehringer-Mannheim) for 1 hour at room temperature. After incubation, the reactions were stopped using 100 mmol/L Tris-HCl (pH 9.5), 100 mmol/L NaCl, and 50 mmol/L MgCl₂. The cells were centrifuged and laid on gelatin-coated slides.

Fluorescence was detected with a Nikon UFX IIA microscope using an excitation range of 450 to 498 nm and an emission range of 550 to 560 nm. The relative percentage of positive isolated myocytes was evaluated visually, and the totals were calculated using counts from a hemocytometer. Between 1000 (for SA node) and 40 000 (ventricular) cells were individually evaluated in each experiment. All numbers in Table 2 represent the results of at least three different experiments. Because of differential yields of cells from various anatomic regions, cells from different ferrets were mixed in some experiments; however, each value in Table 2 is derived from cells isolated from at least three different ferret hearts. Where appropriate, confidence limits between experiments were calculated using an unpaired Student's t test. Differences were taken to be significant at P.01. Images were photographed on 400 ASA color film. Photographs were scanned using a Hewlett-Packard ScanJet IIC and reproduced for publication using Adobe Photoshop.

View this table: [in this window] [in a new window]   Table 2. Abundance and Distribution of K+ Channel Subunit mRNA in Cardiac Myocytes

Additional controls were run with some of the probes. Preincubation of the fixed cells with 100 µg/mL RNase A (37°C for 30 minutes) abolished the hybridization signal with Kv1.2, Kv1.3, Kv1.4, Kv1.5, and the cardiac form of troponin I (TnI_C) antisense probes. To test the fluorescent signal for quenching, cells were hybridized with the TnI_C, Kv1.4, Kv1.5, ERG, and IRK antisense probes, stained, and incubated with reticulocyte lysate as described previously.³⁷

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
The prevalence and distribution of voltage-gated K⁺ channel subunit mRNA transcripts in cardiac myocytes from different regions of the ferret heart is shown in Table 2, and examples of probed cells are shown in the Figure. Several control experiments were performed to ensure the validity of our results. All experiments included the corresponding sense probe. In no experiment did any sense probe give a visually detectable signal (panels A through D), suggesting that the observed signals from the antisense probe (panels E through R) were due to specific hybridization. Additionally, several antisense probes were hybridized after treatment of the myocytes with RNase A. These also gave no detectable signal, showing that the hybridization signals were RNA dependent (data not shown).

View larger version (39K): [in this window] [in a new window]   Figure 1. In situ hybridization of isolated ferret myocytes. A through D, sense probes; E through R, antisense probes. Panels A and E show Kv1.1 with cells from SA node; B and F, Kv1.3 (right atrial cells); C and G, Kv1.4 (right atrial cells); and D and H, Kv1.5 (right atrial cells). Cells in panels I through N were derived from right ventricle. Panel I shows Kv3.1; J, Kv3.2; K, Kv3.3; L, Kv3.4; M, IRK; and N, ERG. Panels O and P show the TnIC probe on cells from left ventricle (O) and SA node (P). Panels Q and R show the TnIS probe on cells from right ventricle (Q) and SA node (R). Arrows show cells counted as negative for hybridization.

To validate our approach further, probes to TnI_C and the slow-twitch form of troponin I (TnI_S) were used as positive controls. Gorza et al³⁸ showed that TnI_C was present in anatomic regions of the mature rat heart rich in working myocytes (atrium and ventricle) and in the SA and atrioventricular nodes as well. In contrast, TnI_S was present only in cells of the conduction system.³⁸ Our results (Table 2; Figure, panels O through R) confirmed these observations in the ferret, where TnI_C was present in 90% of myocytes (except in the septa) and TnI_S was present in the SA node (54.1%) but virtually absent from other anatomic regions. Contrary to expectations, we were not able to detect TnI_C in 10% of myocytes from the atrium or ventricle. Although it is possible that some myocytes do not contain this message, a more likely explanation is that some cells were compromised during preparation, resulting in a few false negatives.

The most intensively studied cardiac K⁺ channels are those of the Kv1 family. Our data (Table 2) show interesting patterns of transcript expression among the Shaker family of K⁺ channels. The most widely distributed K⁺ channel transcripts in the ferret heart are Kv1.5 (69% to 86%) and Kv1.4 (46% to 94%). Both Kv1.5 and Kv1.4 (Figure, panels C and D and panels G through H) are fairly evenly distributed among myocytes from different regions of the heart, except for the relatively low abundance of Kv1.4 in the atrial and ventricular septa. Kv1.2 is also widely distributed in the atrium and ventricle. Cells expressing Kv1.1 (Figure, panels A and E), Kv1.3 (panels B and F), and Kv1.6 were all rare in atrium and ventricle, with the most abundant being Kv1.3 in the right atrium (16.5%). The pattern of Kv1.3 channel mRNA expression differed markedly from the free walls of the atrium and ventricle to septum and SA node (P.01). Both Kv1.2 and Kv1.4 are expressed at lower levels in the septa, whereas Kv1.3 expression is higher in the septa than in the free walls of the atria and ventricles (P.01). More dramatically, Kv1.1 and Kv1.6, which are very rare elsewhere in the heart, are quite common in the SA node.

Transcripts from the three other classes of Shaker-type channels were also expressed in ferret myocytes. Myocytes containing Kv2 channel mRNA were uniformly distributed throughout the heart, with myocytes expressing Kv2.1 being twofold to threefold more abundant than those expressing Kv2.2. Surprisingly, the four known members of the Kv3 (Figure, panels I through L) family are also expressed in myocytes throughout the heart. Kv3.4 shows the most striking regional variation; ventricular myocytes expressing Kv3.4 are roughly threefold more common in the ventricle than in the atrium (P.01). All three known members of the Kv4 family are expressed in the ferret heart, with Kv4.2 being the most abundant (P.01). The transcript of Kv5.1 was most common in the right atrium (46.4%) and rarest in the atrial septum (21.5%). Kv6.1 was less abundant. It was present in 28.4% of SA nodal cells and in <16% of cells in the other anatomic regions.

Recent studies have shown that besides the Shaker-type K⁺ channels, several other proteins may participate in the generation of certain cardiac K⁺ currents. These include members of the IRK family of inward rectifying channels (two membrane-spanning segments)³⁴ and the minK protein (with only a single membrane-spanning segment).^{27 28} Essentially all ventricular myocytes express some member of the IRK family (Figure, panel M), which is also common in the atrium; interestingly, it is nearly absent (6.6±0.6%) from the SA node, consistent with the virtual absence of inward rectifying current (I_K1) in this region.³⁹ The minK protein, which has been proposed to be responsible for I_Ks^{27 28} or a possible cofactor of ERG,⁴⁰ is most common in the SA node, followed by atrium, and then ventricle.

Two channels deserving of special attention are ERG and KvLQT1; mutations in each of these channels are responsible for two of the forms of familial long-QT syndrome.^{20 21} Our results show that ERG (Figure, panel N) is uniformly expressed in about half the myocytes throughout the heart, whereas KvLQT1 is somewhat more common, present in roughly 70% of right atrial and ventricular myocytes and in 50% to 60% in the other regions.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The results of the present study suggest that mRNAs encoding most known voltage-gated K⁺ channels can be found in a substantial portion of ferret cardiac myocytes. We have also shown that the pattern of expression can vary considerably between anatomic regions. Our approach to detection of K⁺ channel gene expression was to use in situ hybridization on enzymatically isolated myocytes obtained from different regions of ferret heart. This approach affords several advantages. The probes are inexpensive and easy to design. Transcripts can be examined in many individual identifiable myocytes isolated from different regions of the heart. Use of the ferret permitted us to conduct these studies on an animal model whose cardiac K⁺ currents are very similar to those of the human. However, only one of the probe sequences was available from ferret. This necessitated extensive use of heterologous probes, which carry an increased risk of nonspecific hybridization. To minimize this risk, most of our probes were designed against human channels (Table 1), which seem to have a high degree of sequence similarity with ferret channels¹⁷ (D.R. Lamson, M.C. Comer, D.L. Campbell, M.J. Morales, and H.C. Strauss, unpublished data, 1995). It was necessary to use rat sequences for five of the probes. Yet even with these heterologous probes, detecting mRNA with the antisense probe was possible, whereas the sense probes never gave a detectable signal, supporting the validity of our approach.

In a previous study, Dixon and McKinnon determined K⁺ channel mRNA levels expressed in different regions of the rat heart.²⁹ However, we detected myocytes containing mRNA for channels not previously thought to exist in the heart, notably members of the Kv3 family. Unfortunately, results obtained by these two methods are not directly comparable. Dixon and McKinnon²⁹ studied RNA isolated from whole hearts by RNase protection assay. This approach is very specific and potentially quantitative. Yet the RNA is necessarily isolated from a large population of cells in whole tissue; it presumably contains all the myocyte mRNA and RNA from other cell types. Our approach of fluorescent in situ hybridization to isolated myocytes has the important advantage of probing for RNA that exists only in single myocytes isolated from specific anatomic regions of the heart. Since we do not know how many myocytes are present in each region and cannot quantify this signal, one cannot draw conclusions about the overall abundance of an individual RNA species. Despite these differences, our results seem to be in general agreement with those of Dixon and McKinnon; the most obvious difference is the presence of Kv3 channel message, which was of "very low" abundance in rat heart when assayed by RNase protection assay. One explanation of this possible discrepancy is a species difference in mRNA expression between ferret and rat. It is also possible that no discrepancy exists. A transcript, expressed at a moderate level in 10% to 20% of individual myocytes, might be of very low abundance when assayed by RNase protection.

The present data suggest that cellular variability in transcript expression may be an important variable in determining the strength of the mRNA signal detected in studies performed on homogenates of whole heart. A subsequent study was performed by Barry et al,⁴¹ who used antibodies to the five channels whose RNA was most abundant. They found that all these proteins were expressed in the rat heart except Kv1.4. Their study highlights an important caution when interpreting in situ hybridization data: mRNA expression may not show a direct correlation with protein expression, although lack of message generally predicts lack of protein expression.

Physiological and Therapeutic Implications
Although our hybridization data do not address whether the variability in transcript expression is cell-to- cell or is due to regional sublocalization, it clearly suggests that differences in K⁺ channel transcript expression could be a significant determinant of differential K⁺ current expression in isolated cardiac myocytes. Rational design of antiarrhythmic drugs will require knowledge of the structure of the channel responsible for generating a target current. Our data suggest that a wider range of potential molecular targets for antiarrhythmic drug action may exist in the heart than previously suspected. Further, the discovery of heteromultimerism among K⁺ channels,^{42 43} the discovery of a cardiac voltage-gated K⁺ channel ß subunit,^{44 45 46} and the realization that non–Shaker-type channels may play an important role in generation of cardiac currents^{23 24 27 28 34} all serve to complicate the process of identification. The traditional criteria for establishing this connection include correlation of physiological and pharmacological properties between cloned channels and native currents.⁴⁷ We propose that understanding the full complexity of the molecular basis of K⁺ current expression in the heart will require coordination of electrophysiological measurements with in situ detection methods for channel subunits in the cell or region of the heart where the current of interest resides.

In conclusion, the present study has used an in situ hybridization technique on myocytes isolated from different regions of the heart. This approach has enabled us to localize mRNA expression of voltage-sensitive K⁺ channels to individual cells, although our data do not predict to what extent the mRNA detected is translated into protein. However, the present study suggests that differences in transcript expression could account for the experimentally observed differential K⁺ current expression between myocytes.⁴⁸ For example, there are significant differences in K⁺ currents between atrial cells,⁴⁹ in the inward rectifier K⁺ current between the ventricle,^{50 51} atrium, and sinus node, and in the I_to between the subepicardium and subendocardium of the human ventricle.⁵² Finally, the present data suggest that molecular information concerning regional and cell-to-cell variability of potential therapeutic targets may ultimately facilitate development of safer and more efficacious antiarrhythmic therapy.

	Acknowledgments

 
This work was supported by NIH grants HL-19216, HL-52874, and HL-54314 and NSF grant CDR8622201. We gratefully acknowledge the invaluable advice provided by Dr J.O. McNamara and J.E. Kraus and the excellent technical assistance of Anne L. Crews.

	Footnotes

 
This manuscript was sent to Harry A. Fozzard, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

Received October 2, 1995; accepted March 21, 1996.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 
1. Schuessler RB, Boineau JP, Bromberg BI, Hand DE, Yamauchi S, Cox JL. Normal and abnormal activation of the atrium. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:543-562.

2. Allessie MA. Reentrant mechanisms underlying atrial fibrillation. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:562-566.

3. Jackman WM, Nakagawa H, Heidbüchel H, Beckman K, McClelland J, Lazzara R. Three forms of atrioventricular nodal (junctional) reentrant tachycardia: differential diagnosis, electrophysiological characteristics, and implications for anatomy of the reentrant circuit. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:620-637.

4. Waldo AL. Atrial flutter: mechanisms, clinical features, and management. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:666-681.

5. Anumonwo JMB, Jalife J. Cellular and subcellular mechanisms of pacemaker activity initiation and synchronization in the heart. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:151-163.

6. Members of the Sicilian Gambit. Antiarrhythmic Therapy: A Pathophysiologic Approach. Armonk, NY: Futura Publishing Co; 1994.

7. Campbell DL, Rasmusson RL, Comer MB, Strauss HC. The cardiac calcium-independent transient outward potassium current: kinetics, molecular properties, and role in ventricular repolarization. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:83-96.

8. Balser JR, Bennett PB, Roden DM. Time-dependent outward current in guinea pig ventricular myocytes. J Gen Physiol. 1990;96:835-863. [Abstract/Free Full Text]

9. Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K⁺ current: differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990;96:195-215. [Abstract/Free Full Text]

10. Sanguinetti MC, Jurkiewicz JK. Lanthanum blocks a specific component of I_K and screens membrane surface charge in cardiac cells. Am J Physiol. 1990;259:H1881-H1889. [Abstract/Free Full Text]

11. Sanguinetti MC, Jurkiewicz NK. Delayed rectifier outward K⁺ current is composed of two currents in guinea pig atrial cells. Am J Physiol. 1991;260:H393-H399. [Abstract/Free Full Text]

12. Kass RS. Delayed potassium channels in the heart: cellular, molecular, and regulatory properties. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:74-82.

13. Wang Z, Fermini B, Nattel S. Rapid and slow components of delayed rectifier current in human atrial myocytes. Cardiovasc Res. 1994;28:1540-1546. [Medline] [Order article via Infotrieve]

14. Fedida D, Wible B, Wang Z, Fermini B, Faust F, Nattel S, Brown AM. Identity of a novel delayed rectifier current from human heart with a cloned K⁺ channel current. Circ Res. 1993;73:210-216. [Abstract]

15. Wang Z, Fermini B, Nattel S. Sustained depolarization-induced outward current in human atrial myocytes: evidence for a novel delayed rectifier K⁺ current similar to Kv1.5 cloned channel currents. Circ Res. 1993;73:1061-1076. [Abstract/Free Full Text]

16. Chandy KG, Gutman GA. Voltage-gated potassium channel genes. In: North RA, ed. Handbook of Receptors and Channels: Ligand and Voltage-Gated Ion Channels. Boca Raton, Fla: CRC Press; 1995:1-71.

17. Comer MB, Campbell DL, Rasmusson RL, Lamson DR, Morales MJ, Zhang Y, Strauss HC. Cloning and characterization of an I_to-like potassium channel from ferret ventricle. Am J Physiol. 1994;267:H1383-H1395. [Abstract/Free Full Text]

18. Beuckelmann DJ, Näbauer M, Erdmann E. Alterations of K⁺ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res. 1993;73:379-385. [Abstract/Free Full Text]

19. Näbauer M, Beuckelmann DJ, Erdmann E. Characteristics of transient outward current in human ventricular myocytes from patients with terminal heart failure. Circ Res. 1993;73:386-394. [Abstract/Free Full Text]

20. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80:795-803. [Medline] [Order article via Infotrieve]

21. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Towbin JA, Moss AJ, Atkinson DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium channel gene: KvLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12:17-23. [Medline] [Order article via Infotrieve]

22. Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A. 1994;91:3438-3442. [Abstract/Free Full Text]

23. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the I_Kr potassium channel. Cell. 1995;81:299-307. [Medline] [Order article via Infotrieve]

24. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92-95.[Abstract/Free Full Text]

25. Kubo Y, Baldwin TJ, Jan YN, Jan LY. Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature. 1993;362:127-133. [Medline] [Order article via Infotrieve]

26. Takumi T, Ohkubo H, Nakanishi S. Cloning of a membrane protein that induces a slow voltage-gated potassium current. Science. 1988;242:1042-1045. [Abstract/Free Full Text]

27. Freeman LC, Kass RS. Expression of a minimal K⁺ channel protein in mammalian cells and immunolocalization in guinea pig heart. Circ Res. 1993;73:968-973. [Abstract/Free Full Text]

28. Varnum MD, Busch AE, Bond CT, Maylie J, Adelman JP. The min K channel underlies the cardiac potassium current I_Ks and mediates species-specific responses to protein kinase C. Proc Natl Acad Sci U S A. 1993;90:11528-11532. [Abstract/Free Full Text]

29. Dixon JE, McKinnon D. Quantitative analysis of potassium channel mRNA expression in atrial and ventricular muscle of rats. Circ Res. 1994;75:252-260. [Abstract/Free Full Text]

30. Jacobson SL, Piper HM. Cell cultures of adult cardiomyocytes as models of the myocardium. J Mol Cell Cardiol. 1986;18:661-678. [Medline] [Order article via Infotrieve]

31. Campbell DL, Rasmusson RL, Qu Y, Strauss HC. The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes, I: basic characterization and kinetic analysis. J Gen Physiol. 1993;101:571-601. [Abstract/Free Full Text]

32. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403-410. [Medline] [Order article via Infotrieve]

33. Pearson WR. Rapid and sensitive sequence comparison with FASTP and FASTA. Methods Enzymol. 1990;183:63-98. [Medline] [Order article via Infotrieve]

34. Wible BA, De Biasi M, Majumder K, Taglialatela M, Brown AM. Cloning and functional expression of an inwardly rectifying K⁺ channel from human atrium. Circ Res. 1995;76:343-350. [Abstract/Free Full Text]

35. Koyama H, Morishige KI, Takahashi N, Zanelli JS, Fass DN, Kurachi Y. Molecular cloning, functional expression and localization of a novel inward rectifier potassium channel in the rat brain. FEBS Lett. 1994;341:303-307. [Medline] [Order article via Infotrieve]

36. Wilkinson DG, ed. In Situ Hybridization: A Practical Approach. 2nd ed. Oxford, England: IRL Press; 1992.

37. NIAID Manual of Tissue Typing Techniques. Washington, DC: National Institutes of Health; 1979.

38. Gorza L, Ausoni S, Merciai N, Hastings KEM, Schiaffino S. Regional differences in troponin I isoform switching during rat heart development. Dev Biol. 1993;156:253-264. [Medline] [Order article via Infotrieve]

39. Noma A, Nakayama T, Kurachi Y, Irisawa H. Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn J Physiol. 1984;34:245-254. [Medline] [Order article via Infotrieve]

40. Yang T, Kupershmidt S, Roden DM. Anti-minK antisense decreases the amplitude of the rapidly activating cardiac delayed rectifier K⁺ current. Circ Res. 1995;77:1246-1253. [Abstract/Free Full Text]

41. Barry DM, Trimmer JS, Merlie JP, Nerbonne JM. Differential expression of voltage-gated K⁺ channel subunits in adult rat heart: relation to functional K⁺ channels? Circ Res. 1994;77:361-369. [Abstract/Free Full Text]

42. Sheng M, Liao YJ, Jan YN, Jan LY. Presynaptic A-current based on heteromultimeric K⁺ channels detected in vivo. Nature. 1993;365:72-75. [Medline] [Order article via Infotrieve]

43. Wang H, Kunkel DD, Martin TM, Schwartzkroin PA, Tempel BL. Heteromultimeric K⁺ channels in terminal and juxtaparanodal regions of neurons. Nature. 1993;365:75-79. [Medline] [Order article via Infotrieve]

44. Morales MJ, Castellino RC, Crews AL, Rasmusson RL, Strauss HC. A novel ß subunit increases rate of inactivation of specific voltage-gated potassium channel subunits. J Biol Chem. 1995;270:6272-6277. [Abstract/Free Full Text]

45. Majumder K, De Biasi M, Wang Z, Wible BA. Molecular cloning and functional expression of a novel K⁺ channel ß-subunit from human atrium. FEBS Lett. 1995;361:13-16. [Medline] [Order article via Infotrieve]

46. England SK, Uebele VN, Koidali J, Bennett PB, Tamkun MM. A novel K⁺ channel ß-subunit (hKvß1.3) is produced via alternative mRNA splicing. J Biol Chem. 1995;270:28531-28534. [Abstract/Free Full Text]

47. Bennett PB, Po S, Snyders DJ, Tamkun MM. Molecular and functional diversity of cloned cardiac potassium channels. Cardiovasc Drugs Ther. 1993;7:585-592.

48. Antzelevitch C, Sicouri S, Lukas A, Nesterenko VV, Liu D-W, Di Diego JM. Regional differences in the electrophysiology of ventricular cells: physiological and clinical implications. In: Zipes DP, Jalife J, eds. Cardiac Electrophysiology: From Cell to Bedside. 2nd ed. Philadelphia, Pa: WB Saunders Co; 1995:228-245.

49. Wang Z, Fermini B, Nattel S. Delayed rectifier outward current and repolarization in human atrial myocytes. Circ Res. 1993;73:276-285. [Abstract/Free Full Text]

50. Giles W, van Ginneken A, Shibata EF. Ionic currents underlying cardiac pacemaker activity: a summary of voltage-clamp data from single cells. In: Nathan RD, ed. Cardiac Muscle: The Regulation of Excitation and Contraction. Orlando, Fla: Academic Press Inc; 1986:1-27.

51. Giles W, Imaizumi Y. Comparison of potassium currents in rabbit atrial and ventricular cells. J Physiol (Lond). 1988;405:123-145. [Abstract/Free Full Text]

52. Näbauer M, Beuckelmann DJ, Überfuhr P, Steinbeck G. Regional differences in current density and rate-dependent properties of the transient outward current in subepicardial and subendocardial myocytes of human left ventricle. Circulation. 1996;93:168-177. [Abstract/Free Full Text]

53. Vallins WJ, Brand NJ, Dabhade N, Butler-Browne G, Yacoub MH, Barton PJ. Molecular cloning of human cardiac troponin I using polymerase chain reaction. FEBS Lett. 1990;270:55-61.

54. Wade R, Eddy R, Shows TB, Kedes L. cDNA sequence, tissue-specific expression, and chromosomal mapping of the human slow-twitch skeletal muscle isoform of troponin I. Genomics. 1990;7:346-357. [Medline] [Order article via Infotrieve]

55. Ramashwami M, Gautam M, Kamb AA, Rudy B, Tanouye MA, Mathew MK. Human potassium channel genes: molecular cloning and functional expression. Mol Cell Neurosci. 1990;1:214-223.

56. Attali B, Romey G, Honoré E, Schmid-Alliana A, Matei MG, Lesage F, Ricard P, Barhanin J, Lazdunski M. Cloning, functional expression, and regulation of two K⁺ channels in human T lymphocytes. J Biol Chem. 1992;267:8650-8657. [Abstract/Free Full Text]

57. Tamkun MM, Knoth KM, Walbridge JA, Kroemer H, Roden DM, Glover DM. Molecular cloning and characterization of two voltage-gated K⁺ channel cDNAs from human ventricle. FASEB J. 1991;5:331-337. [Abstract]

58. Grupe A, Schroter KH, Ruppersberg JP, Stocker M, Drewes T, Beckh S, Pongs O. Cloning and expression of a human voltage-gated potassium channel: a novel member of the RCK potassium channel family. EMBO J. 1990;9:1749-1756. [Medline] [Order article via Infotrieve]

59. Albrecht B, Lorra C, Stocker M, Pongs O. Cloning and characterization of a human delayed rectifier potassium channel gene. Recept Chan. 1993;1:99-110. [Medline] [Order article via Infotrieve]

60. Hwang PM, Glatt CE, Bredt DS, Yellen G, Snyder SH. A novel potassium channel with unique localization in mammalian brain: molecular cloning and characterization. Neuron. 1992;8:473-481. [Medline] [Order article via Infotrieve]

61. Ried T, Rudy B, Vega-Saenz de Miera E, Lau D, Ward DC, Sen K. Localization of a highly conserved human potassium channel gene (NGK2-KV4; KCNC1) to chromosome 11p15. Genomics. 1993;15:405-411. [Medline] [Order article via Infotrieve]

62. McCormack T, Vega-Saenz de Miera EC, Rudy B. Molecular cloning of a member of a third class of Shaker-family K⁺ channel genes in mammals. Proc Natl Acad Sci U S A. 1990;87:5227-5231. [Abstract/Free Full Text]

63. Lee JE, Garbutt JH, Phillips KL, Garbutt JH, Roses AD. H. sapiens chromosome 19 potassium channel gene (partial). GenBank accession Z11585.

64. Vega-Saenz de Miera E, Moreno H, Fruhling D, Kentros C, Rudy B. Cloning of ShIII (Shaw-like) cDNAs encoding a novel high-voltage-activating, TEA-sensitive, type-A K⁺ channel. Proc R Soc Lond B Biol Sci. 1992;248:9-18. [Medline] [Order article via Infotrieve]

65. Lennon GG, Auffray C, Polymeropoulos M, Soares MB. The I.M.A.G.E. consortium: an integrated molecular analysis of genomes and their expression. Genomics. In press.

66. Baldwin TJ, Tsaur ML, Lopez GA, Jan YN, Jan LY. Characterization of a mammalian cDNA for an inactivating voltage-sensitive K⁺ channel. Neuron. 1991;7:471-483. [Medline] [Order article via Infotrieve]

67. Serodio P, Rudy B. Cloning, expression and distribution of Kv4.3, a new mammalian subunit of the A-type, low voltage-activating potassium channels. J Neurophysiol. In press.

68. Drewe JA, Verma S, Frech G, Joho RH. Distinct spatial and temporal expression patterns of K⁺ channel mRNAs from different subfamilies. J Neurosci. 1992;12:538-548. [Abstract]

69. Murai T, Kakizuka A, Takumi T, Ohkubo H, Nakanishi S. Molecular cloning and sequence analysis of human genomic DNA encoding a novel membrane protein which exhibits a slowly activating potassium channel activity. Biochem Biophys Res Commun. 1989;161:176-181.[Medline] [Order article via Infotrieve]

This article has been cited by other articles:

				G. C. L. Bett and R. L. Rasmusson Modification of K+ channel-drug interactions by ancillary subunits J. Physiol., February 15, 2008; 586(4): 929 - 950. [Abstract] [Full Text] [PDF]

				L. Neshatian, Y. M. Leung, Y. Kang, X. Gao, H. Xie, R. G. Tsushima, H. Y. Gaisano, and N. E. Diamant Distinct modulation of Kv1.2 channel gating by wild type, but not open form, of syntaxin-1A Am J Physiol Gastrointest Liver Physiol, May 1, 2007; 292(5): G1233 - G1242. [Abstract] [Full Text] [PDF]

				G. C. L. Bett, M. J. Morales, D. L. Beahm, M. E. Duffey, and R. L. Rasmusson Ancillary subunits and stimulation frequency determine the potency of chromanol 293B block of the KCNQ1 potassium channel J. Physiol., November 1, 2006; 576(3): 755 - 767. [Abstract] [Full Text] [PDF]

				S. P. Patel and D. L. Campbell Transient outward potassium current, 'Ito', phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms J. Physiol., November 15, 2005; 569(1): 7 - 39. [Abstract] [Full Text] [PDF]

				S. C. Hebert, G. Desir, G. Giebisch, and W. Wang Molecular Diversity and Regulation of Renal Potassium Channels Physiol Rev, January 1, 2005; 85(1): 319 - 371. [Abstract] [Full Text] [PDF]

				C. Marionneau, B. Couette, J. Liu, H. Li, M. E. Mangoni, J. Nargeot, M. Lei, D. Escande, and S. Demolombe Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart J. Physiol., January 1, 2005; 562(1): 223 - 234. [Abstract] [Full Text] [PDF]

				S. L. Archer, X.-C. Wu, B. Thebaud, A. Nsair, S. Bonnet, B. Tyrrell, M. S. McMurtry, K. Hashimoto, G. Harry, and E. D. Michelakis Preferential Expression and Function of Voltage-Gated, O2-Sensitive K+ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction: Ionic Diversity in Smooth Muscle Cells Circ. Res., August 6, 2004; 95(3): 308 - 318. [Abstract] [Full Text] [PDF]

				M. T. Perez-Garcia, O. Colinas, E. Miguel-Velado, A. Moreno-Dominguez, and J. R. Lopez-Lopez Characterization of the Kv channels of mouse carotid body chemoreceptor cells and their role in oxygen sensing J. Physiol., June 1, 2004; 557(2): 457 - 471. [Abstract] [Full Text] [PDF]

				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]

				M. Madeja, T. Leicher, P. Friederich, M. A. Punke, W. Haverkamp, U. Musshoff, G. Breithardt, and E.-J. Speckmann Molecular Site of Action of the Antiarrhythmic Drug Propafenone at the Voltage-Operated Potassium Channel Kv2.1 Mol. Pharmacol., March 1, 2003; 63(3): 547 - 556. [Abstract] [Full Text] [PDF]

				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]

				R. B Clark, A. Tremblay, P. Melnyk, B. G Allen, W. R Giles, and C. Fiset T-tubule localization of the inward-rectifier K+ channel in mouse ventricular myocytes: a role in K+ accumulation J. Physiol., December 15, 2001; 537(3): 979 - 992. [Abstract] [Full Text] [PDF]

				Members of the Sicilian Gambit New Approaches to Antiarrhythmic Therapy, Part II: Emerging Therapeutic Applications of the Cell Biology of Cardiac Arrhythmias Circulation, December 11, 2001; 104(24): 2990 - 2994. [Abstract] [Full Text] [PDF]

				Members of the Sicilian Gambit New approaches to antiarrhythmic therapy; emerging therapeutic applications of the cell biology of cardiac arrhythmias Eur. Heart J., December 1, 2001; 22(23): 2148 - 2163. [Abstract] [PDF]

				Members of the Sicilian Gambit New approaches to antiarrhythmic therapy: emerging therapeutic applications of the cell biology of cardiac arrhythmias Cardiovasc Res, December 1, 2001; 52(3): 345 - 360. [Abstract] [Full Text] [PDF]

				J. J Zaritsky, J. B Redell, B. L Tempel, and T. L Schwarz The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes J. Physiol., June 15, 2001; 533(3): 697 - 710. [Abstract] [Full Text] [PDF]

				M. Nabauer Tuning Repolarization in the Heart : A Multitude of Potassium Channels and Regulatory Pathways Circ. Res., March 16, 2001; 88(5): 453 - 455. [Full Text] [PDF]

				J.-H. Schultz, T. Volk, and H. Ehmke Heterogeneity of Kv2.1 mRNA Expression and Delayed Rectifier Current in Single Isolated Myocytes From Rat Left Ventricle Circ. Res., March 16, 2001; 88(5): 483 - 490. [Abstract] [Full Text] [PDF]

				L. Yue, Z. Wang, H. Rindt, and S. Nattel Molecular evidence for a role of Shaw (Kv3) potassium channel subunits in potassium currents of dog atrium J. Physiol., September 15, 2000; 527(3): 467 - 478. [Abstract] [Full Text] [PDF]

				W. Han, Z. Wang, and S. Nattel A comparison of transient outward currents in canine cardiac Purkinje cells and ventricular myocytes Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H466 - H474. [Abstract] [Full Text] [PDF]

				H. Dobrzynski, S. M. Rothery, D. D.R. Marples, S. R. Coppen, Y. Takagishi, H. Honjo, M. M. Tamkun, Z. Henderson, I. Kodama, N. J. Severs, et al. Presence of the Kv1.5 K+ Channel in the Sinoatrial Node J. Histochem. Cytochem., June 1, 2000; 48(6): 769 - 780. [Abstract] [Full Text]

				K. Ono, S. Shibata, and T. Iijima Properties of the delayed rectifier potassium current in porcine sino-atrial node cells J. Physiol., April 1, 2000; 524(1): 51 - 62. [Abstract] [Full Text] [PDF]

				A. D. Wickenden, P. Lee, R. Sah, Q. Huang, G. I. Fishman, and P. H. Backx Targeted Expression of a Dominant-Negative Kv4.2 K+ Channel Subunit in the Mouse Heart Circ. Res., November 26, 1999; 85(11): 1067 - 1076. [Abstract] [Full Text] [PDF]

				H. M. Himmel, E. Wettwer, Q. Li, and U. Ravens Four different components contribute to outward current in rat ventricular myocytes Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H107 - H118. [Abstract] [Full Text] [PDF]

				R Kaprielian, A D Wickenden, Z Kassiri, T G Parker, P P Liu, and P H Backx Relationship between K+ channel down-regulation and [Ca2+ ]i in rat ventricular myocytes following myocardial infarction J. Physiol., May 15, 1999; 517(1): 229 - 245. [Abstract] [Full Text] [PDF]

				D. M. Roden and S. Kupershmidt From genes to channels: normal mechanisms Cardiovasc Res, May 1, 1999; 42(2): 318 - 326. [Abstract] [Full Text] [PDF]

				M. V. Brahmajothi, D. L. Campbell, R. L. Rasmusson, M. J. Morales, J. S. Trimmer, J. M. Nerbonne, and H. C. Strauss Distinct Transient Outward Potassium Current (Ito) Phenotypes and Distribution of Fast-inactivating Potassium Channel Alpha Subunits in Ferret Left Ventricular Myocytes J. Gen. Physiol., April 1, 1999; 113(4): 581 - 600. [Abstract] [Full Text] [PDF]

				Z. Wang, J. Feng, H. Shi, A. Pond, J. M. Nerbonne, and S. Nattel Potential Molecular Basis of Different Physiological Properties of the Transient Outward K+ Current in Rabbit and Human Atrial Myocytes Circ. Res., March 19, 1999; 84(5): 551 - 561. [Abstract] [Full Text] [PDF]

				S. G. Priori, J. Barhanin, R. N. W. Hauer, W. Haverkamp, H. J. Jongsma, A. G. Kleber, W. J. McKenna, D. M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Part III Circulation, February 9, 1999; 99(5): 674 - 681. [Full Text] [PDF]

				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]

				S.G. Priori, J. Barhanin, R.N.W. Hauer, W. Haverkamp, H.J. Jongsma, A.G. Kleber, W.J. McKenna, D.M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management Eur. Heart J., February 1, 1999; 20(3): 174 - 195. [PDF]

				N. I. Nenov, W. J. Crumb Jr, J. D. Pigott, L. H. Harrison Jr, and C. W. Clarkson Quinidine Interactions With Human Atrial Potassium Channels : Developmental Aspects Circ. Res., December 14, 1998; 83(12): 1224 - 1231. [Abstract] [Full Text] [PDF]

				L. M. Pacioretty and R. F. Gilmour Jr. Restoration of transient outward current by norepinephrine in cultured canine cardiac myocytes Am J Physiol Heart Circ Physiol, November 1, 1998; 275(5): H1599 - H1605. [Abstract] [Full Text] [PDF]

				J. Feng, L. Yue, Z. Wang, and S. Nattel Ionic Mechanisms of Regional Action Potential Heterogeneity in the Canine Right Atrium Circ. Res., September 7, 1998; 83(5): 541 - 551. [Abstract] [Full Text] [PDF]

				M. Nabauer and S. Kaab Potassium channel down-regulation in heart failure Cardiovasc Res, February 1, 1998; 37(2): 324 - 334. [Abstract] [Full Text] [PDF]

				T. Y. Nakamura, W. A. Coetzee, E. Vega-Saenz De Miera, M. Artman, and B. Rudy Modulation of Kv4 channels, key components of rat ventricular transient outward K+ current, by PKC Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1775 - H1786. [Abstract] [Full Text] [PDF]

				D. J. Baro, R. M. Levini, M. T. Kim, A. R. Willms, C. C. Lanning, H. E. Rodriguez, and R. M. Harris-Warrick Quantitative Single-Cell-Reverse Transcription-PCR Demonstrates That A-Current Magnitude Varies as a Linear Function of shal Gene Expression in Identified Stomatogastric Neurons J. Neurosci., September 1, 1997; 17(17): 6597 - 6610. [Abstract] [Full Text] [PDF]

				M. V. Brahmajothi, M. J. Morales, K. A. Reimer, and H. C. Strauss Regional Localization of ERG, the Channel Protein Responsible for the Rapid Component of the Delayed Rectifier, K+ Current in the Ferret Heart Circ. Res., July 19, 1997; 81(1): 128 - 135. [Abstract] [Full Text]

				R. Coronel, T. Opthof, P. Taggart, J. Tytgat, and M. Veldkamp Differential electrophysiology of repolarisation from clone to clinic Cardiovasc Res, March 1, 1997; 33(3): 503 - 517. [PDF]

				S. W. Yeola and D. J. Snyders Electrophysiological and pharmacological correspondence between Kv4.2 current and rat cardiac transient outward current Cardiovasc Res, March 1, 1997; 33(3): 540 - 547. [Abstract] [PDF]

				R. S. Wymore, G. A. Gintant, R. T. Wymore, J. E. Dixon, D. McKinnon, and I. S. Cohen Tissue and Species Distribution of mRNA for the IKr-like K+ Channel, erg Circ. Res., February 1, 1997; 80(2): 261 - 268. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brahmajothi, M. V. Articles by Strauss, H. C. Search for Related Content PubMed PubMed Citation Articles by Brahmajothi, M. V. Articles by Strauss, H. C.