© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Can PKA activators rescue Na+ channel function in epicardial border zone cells that survive in the infarcted canine heart?
aDepartment of Pharmacology, Columbia University, New York, NY, United States
bCenter for Molecular Therapeutics, Columbia University, New York, NY, United States
* Corresponding author. Department of Pharmacology, Columbia College of Physicians and Surgeons, 630 West 168th ST., New York, NY 10032, United States. Tel.: +1 212 305 7907; fax: +1 212 305 0529. Email address: pab4{at}columbia.edu
Received 26 February 2004; revised 22 June 2004; accepted 24 June 2004
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Abstract |
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 Top Abstract 1. Introduction2. Methods3. Results4. DiscussionReferences |
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Objective and methods: In this study, we investigated the effects of a PKA stimulating cocktail on sodium currents from normal epicardial cells (NZs) and on those from cells dispersed from the epicardial zone of the 5-day infarcted canine heart (IZs). To do so, we used whole-cell voltage-clamp techniques.
Results: During superfusion with the PKA activator cocktail, peak sodium current (INa) density significantly increased by 32±5.3% (NZs) and 17±5.4% (IZs). However, despite this increase, IZ peak INa still was not fully restored to NZ values. In both cell types, the density effect was accompanied by a shift in I/Imax curves, as well as a slowing in recovery from inactivation. Inactivation from a closed state was accelerated. Furthermore, in the presence of chloroquine, which is known to interrupt intracellular vesicular traffic, PKA activator effects to augment INa were only partially inhibited in NZs but abolished in IZs. To understand whether the phosphorylation status of basal Na+ channels in the two cell groups differed, the effects of okadaic acid and PP2A1 were studied. Results suggest that in IZs, Na+ channels in the basal state are already phosphorylated.
Conclusions: PKA stimulation of INa of the remodeled IZ does augment current density possibly by augmenting the trafficking of channels to an active site on the membrane. However, the resulting INa, while partially rescued, is not similar to the potentiated INa of NZs. Specific kinetic changes also occur with the PKA stimulation of IZs and results with okadaic acid and PP2A1 suggest that in their remodeled state, Na+ channels in IZs are already phosphorylated.
KEYWORDS Myocardial infarction; Ion channels; Remodeling; Arrhythmias
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1. Introduction |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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Five days after total coronary artery occlusion, rapid sustained ventricular tachycardias can be induced by electrical stimulation in the canine heart. These arrhythmias occur due to reentrant excitation in the thin layer of surviving cells called the epicardial border zone (EBZ) [1]. Recent data have suggested that the function of several ionic currents is modified in these cells, a process called electrical remodeling [2]. Computational analysis, revealing the importance of these ionic current changes, has recently been published [3] and showed that the ionic determinant of the phenomena measured in the epicardial border zone cells (IZs) called postrepolarization refractoriness is related to the reduced density and abnormal sodium current (INa) kinetics of the 5-day EBZ cells [4]. These kinetic changes underlie the marked use-dependent reduction in INa consistent with the findings in the in situ EBZ [5]. Marked conduction slowing and altered excitability are common characteristics of this arrhythmic substrate [1].
The use of pore ion channel blocking drugs to reduce INa, (flecainide, etc.) as antiarrhythmic agents in this post-MI setting is not appropriate, because their use exacerbates rather than terminates reentrant excitation [6]. Therefore, here we tested whether we could restore Na+ channel function in this setting by "rescuing" its function in the EBZ cells. Restoring excitability could be antiarrhythmic. Rescuing ion channel function has proven a useful approach in some forms of inherited ion channel disorders (e.g., Ref. [7]).
Recent experimental data suggest that activation of protein kinase A (PKA) increases INa [8] by increasing the number of Na+ channels at the cell membrane. The basis of the PKA-mediated potentiation of recombinant INa may involve increased trafficking of the Na channel protein to the membrane [8]. Thus, in this study, we examined the effects of potent PKA activation on INa of both normal cells (NZs) and IZs. We hypothesized that PKA stimulation in IZs would improve INa function.
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2. Methods |
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2.1 Cell preparation
This investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the U.S. NIH Pub. No. 85–23, 1996.
Healthy mongrel dogs (12 to 15 kg, 2 to 3 years old) were used in these studies. Under isoflurane anesthesia (30 mg/kg) and sterile conditions, myocardial infarction was produced by a two-step total occlusion of the left coronary artery using the Harris procedure [9]. Dogs were treated with lidocaine (2 mg/kg IV) if multiple ventricular beats occurred at the time of the surgical procedure. Five days after surgery, a cardiectomy was performed with the dogs under sodium pentobarbital (30 mg/kg IV) anesthesia.
Single calcium-tolerant cells were dispersed from EBZ sections (IZs) using a modification of our previously described method [5,10,11]. Briefly, the tissue was rinsed twice in a Ca2+-free solution containing (in mM) NaCl 115, KCl 5, sucrose 35, dextrose 10, N-2-hydroxyethylpiperazine-N'-2-ethanosulfonic acid (HEPES) 10, taurine 4, pH 6.95, to remove blood. Then, it was triturated in 20 ml of enzyme-containing solution (collagenase type II from Worthington Biochemical, Lakewood, NJ; 0.38 mg/ml; 36–37 °C) for 30 min, after which, the solution was decanted and discarded. Only, this first solution contained 0.01 mg/ml protease (Sigma). The second trituration was discarded after 30 min. The next six to seven triturations were each done for 15 min. Each time, the solution was centrifuged at 500 rpm for 3 min to collect the supernatant and dispersed cells. Resuspension solution was changed every 30 min for solutions containing increasing concentrations of Ca2+ (50 to 500 µmol/l). With this procedure, the viable cell yield was approximately 30–40%. For normal control ventricular cell group (NZs), only rod-shaped cells with staircase ends, clear striations, and surface membranes free from blebs were used for this study. IZs chosen for study, however, had a ruffled appearance, were less rodlike appearing, and had somewhat irregular cross striations and small dark droplets on the membrane [11].
2.2 Experimental conditions
For study, an aliquot of cells was transferred onto a polylysine-coated glass coverslip placed at the bottom of a 0.5-ml tissue chamber, which had been mounted on the stage of a Nikon inverted microscope (Nikon Diaphot, Tokyo, Japan). Myocytes were continuously superfused (2 to 3 ml/min) with normal Tyrode's solution containing (in mmol/l) NaCl 137, NaHCO3 24, NaH2PO4 1.8, MgCl2 0.5, CaCl2 2.0, KCl 4.0, and dextrose 5.5 (pH 7.4). The solution was bubbled with 5% CO2/95% O2. Temperature was monitored continuously and maintained at 19.0±0.5 °C for proper voltage control. Patch pipettes were made from borosilicate thin wall glass (Sutter Instrument; outer diameter, 1.5 mm; inner diameter, 1.1 mm) using a Flaming/Brown-type horizontal puller (model P-87, Sutter Instrument) and polished (type MF-83, Narishige, Scientific Instrument Laboratory) before use. Pipette resistances ranged between 0.6 and 1.0 M
when filled with an internal solution that had the following composition (mmol/l): CsOH 125, aspartic acid 125, tetraethylammonium chloride 20, HEPES 10, Mg-ATP 5, EGTA 10, and phosphocreatine 3.6 (pH 7.3 with CsOH). After the formation of the gigaohm seal, the stray capacitance was electronically nulled. The cell membrane under the pipette tip was then ruptured by a brief increase in suction, forming the whole-cell recording configuration. A period of 5–10 min was then allowed for intracellular dialysis to begin before switching to the low-Na+ recording solution (mmol/l): NaCl 5, MgCl2 1.2, CaCl2 1.8, tetraethylammonium chloride 125, CsCl 5, HEPES 20, glucose 11, 4-aminopyridine 3.0, and MnCl2 2.0 (pH 7.3 with CsOH), designed for proper INa measurements. Mn2+ is known to affect INa, and previous experiments showed that the Mn2+ effect on INa in IZs was similar to its effect in NZs [10]. With this combination of external and internal solutions, INa would be of manageable size and would be isolated from other possible contaminating currents.
2.3 Voltage-clamp and recording techniques
Whole-cell INa was recorded using the whole-cell patch-clamp technique as described [10]. Voltage-clamp experiments were performed with an Axopatch 200A clamp amplifier (Axon Instruments). The membrane capacity (in pF) of each cell was measured in the Cs+-rich solution by integrating the area under a capacitative transient induced by a 10-mV hyperpolarizing clamp step (from –100 to –110 mV) and dividing this area by voltage step. Current amplitude data of each cell was normalized to its cell capacitance [current density (pA/pF)]. Averaged cell capacitances were 159±6.6 pF in NZs (n=16) and 197±9.0 pF in IZs(n=14; p<0.05). The average time constant of decay of the capacitative transient was 0.155±0.01 ms in NZs and 0.158±0.01 ms in IZs. Therefore, the average residual series resistance was 0.97±0.05 M for NZs and 0.82±0.05 M for IZs. Thus, average steady state voltage error resulting from series resistance was 1.48±0.16 mV for NZs and 0.91±0.18 mV for IZs (p=0.023).
For consideration of the voltage control, we used 5 mmol/l extracellular Na+ concentration, a maintained temperature of 19±0.5 °C, and patch pipettes with resistances no larger than 1.0 M. Furthermore, we did not choose large cells. If experiments demonstrating inadequate voltage control, e.g., a "threshold phenomenon" near the voltage range for Na+ channel activation, and/or an inappropriately steep increase in current amplitude in the negative slope region of the current–voltage relationship curve, data were discarded. Whole-cell INa was obtained by subtracting the traces elicited with comparable voltage steps containing no current (using prepulse to inactivate the Na+ channels) from the raw current traces [10]. In this way, the cell capacitance and linear leakage, if present, were subtracted.
2.4 Experimental protocols
Under our conditions, time-dependent changes of Na+ channel kinetics, including a shift of the availability curve (I/Imax curve) in the hyperpolarizing direction, have been reported [10]. Typically, these changes occur within minutes after membrane rupture. We have previously established the degree of shift of I/Imax inactivation curves with time after membrane rupture to be 0.11 to 0.14 mV/min in NZs and IZs. Therefore, as before, peak current data are collected between 20 and 50 min after membrane rupture, and we took care to match the averaged time after membrane rupture at which data were collected for the cells in the two groups (see legends).
Peak current density in cells from the two groups, I–V data, activation data, "steady-state" availability (I/Imax), the time course of inactivation directly from the "closed state", and time course of recovery of INa from steady-state inactivation were assessed using previously published protocols [4,5].
2.5 Drugs and chemicals
8-chlorophenylthio cAMP (8-cpt-cAMP), 3-isobutyl-1-methylxanthine (IBMX), forskolin, and chloroquine were obtained from Sigma. Both IBMX and forskolin were dissolved in DMSO to generate 400 and 20 mmol/l stock solutions, respectively (total bath concentration of DMSO was 0.3%). To stimulate PKA, cells were superfused with a cocktail of these kinase activators (8-cpt-cAMP 200 µmol/l, IBMX 1 mmol/l, and forskolin 10 µmol/l; [8]).
2.6 Statistics
All values are represented as mean±S.E.M. A value of p<0.05 was considered statistically significant. For two-sample comparison, an unpaired t test was used to compare a single mean value between the two independent cell groups. A paired t test was used to compare the mean values obtained from the same cells before and after drug intervention. For multiple comparison, an ANOVA was used to determine that the sample mean values between groups were significantly different from each other. If so, a modified t test with Bonferroni correction was used (Sigmastat, Jandel Scientific).
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3. Results |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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3.1 Effects of PKA activator cocktail on INa density and kinetics
Fig. 1 shows a family of INa tracings obtained in a typical NZ (panel A) and IZ (panel B). The averaged amplitude of peak INa was reduced significantly in IZs (–1164.7±318.8 pA, n=14) versus that in NZs (–1674.8±219.8 pA, n=16, p<0.05). Fig. 1C,D illustrate the averaged normalized INa density–voltage relationship curves in NZs and IZs. For both cell types, current activation occurred at –55 mV, currents gradually increased and reached their peak at Vt=–20 to 25 mV. The peak INa was –10.0±1.1 pA/pF in NZs and –5.6±1.2 pA/pF in IZs (p<0.05; Table 1). Fig. 2A shows the time course of the PKA "cocktail" effect on INa in a subset of NZs and IZs. PKA activators significantly increased INa density after 5 min of superfusion. The effect saturated by 15–25 min. Superfusion of cells with 0.3% DMSO, the solvent for forskolin and IBMX, had no significant effect on INa (Fig. 2B). Thus, dialysis or solvent-induced changes in INa cannot account for PKA activator effects on INa in Fig. 1A,B. During superfusion with the PKA cocktail, peak INa density significantly increased in NZs (by 32±5.3%) and in IZs (17±5.4%; Fig. 1C,D).
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Fig. 3A shows average normalized INa values for each group plotted as a function of Vt. PKA cocktail significantly shifted the V0.5 of the gNa curves in a hyperpolarizing direction (NZs: from –26.6±1.2 to –30.3±0.8 mV, p<0.05; IZs: from –25.4±2.0 to –28.6±1.4 mV, p<0.05) and had a modest effect on the slope factor (K: NZs: from 7.26±0.16 to 7.47±0.2, p>0.05; IZs: from 8.28±0.22 to 7.98±0.18, p<0.05). This effect was not seen with DMSO alone (data not shown). We used a double-pulse protocol to determine steady-state inactivation (I/Imax) curves in a subset of cells from each group. In Fig. 3B,C, average normalized INa values for each group were plotted as a function of Vc. The average maximally available INa (at Vc=–120 mV) was –10.4±1.1 pA/pF in NZs (n=16) and –6.0±1.0 pA/pF in IZs (n=11; p<0.05). The PKA cocktail significantly shifted the V0.5 of the I/Imax curves in hyperpolarizing direction in both groups (NZs: from –75.4±1.2 to –80.3±1.1 mV, p<0.05; IZs: from –78.5±1.5 to –82.6±1.3 mV, p<0.05). This effect was not seen with DMSO alone (data not shown).
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3.2 Closed state inactivation and recovery from inactivation
To examine the effects of PKA activators on Na+ channel inactivation from a closed state, a clamp protocol consisting of a conditoning prepulse to –60 mV (subthreshold voltage) of increasing duration was followed by a 2-ms interval to Vh=–100 mV and then to a test pulse of –25 mV (Fig. 4). For both NZs and IZs, INa amplitude is reduced as the duration of the conditoning prepulse is increased, indicating that more and more channels become inactivated. Furthermore, this process is accelerated in the presence of PKA activators in both cell types (Fig. 4).
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The time course of recovery of INa from steady-state inactivation was studied using a conventional double-pulse protocol. Two levels of VH (–90 and –100 mV) were used in this series of experiments. The time course of recovery from inactivation was significantly slower in IZs than in NZs in the absence of the PKA activator cocktail (Table 2). PKA activators significantly slowed the time constants of recovery (
1 and 2) in both cell types. Interestingly, NZs+PKA recovery kinetics approached those of IZ kinetics in the drug-free state (Table 2).
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3.3 Pathway of PKA activator effect on Na+ channel function
PKA activators could increase cardiac INa through at least two different pathways. One is by promoting direct phosphorylation on the I–II loop of
-subunit (Ser 525 and 528, human) [12,13]. Another is by acceleration of trafficking of the Na+ channel -subunit protein from ER to the plasma membrane [8]. To test whether PKA activators increase INa by promoting trafficking of Na+ channel proteins to the active sites, we determined the effects of the PKA activators on INa in the presence of chloroquine (100 µmo/l), an inhibitor of cell trafficking [8]. In NZs in the presence of chloroquine, PKA activators still significantly increased peak INa by 20% (Fig. 5 and Table 3). In contrast, in IZs in the presence of chloroquine, PKA activators had no significant effect to increase INa (Table 3). In fact, PKA activators in the presence of chloroquine caused a small decrease of INa.
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Thus, in the presence of the chloroquine, which is known to interrupt intracellular vesicular traffic [8], PKA activator effects to augment INa are partially inhibited in NZs (by 10%) and totally abolished in IZs.
3.4 Effects of okadaic acid (OA) and protein phosphatase 2A1 (PP2A1) on INa in NZs and IZs
The differing effects of PKA stimulation on INa in NZs and IZs suggest that the phosphorylation status of the basal Na+ channel may differ between NZs and IZs. Therefore, we tested in a subgroup of cells, the effects of the phosphatase inhibitor okadaic acid (OA) on INa in NZs and IZs. OA (1 µmol/l) in the internal pipette solution produced INa in NZs of –14.3±1.9 pA/pF (n=14). This is greater than INa in NZs without OA, –10±1.9 pA/pF, n=16. In contrast, OA had no effect on INa in IZs (IZs without OA –5.6±1.1 pA/pF, IZs with OA in pipette –5.1±1.3 (n=5) pA/pF, p>0.05).
PP2A1 is known to cause dephosphorylation of cardiac ion channels (e.g., Ref. [14]), therefore if basal Na+ channels in IZs are basally phosphorylated, then PP2A1 by causing dephosphorylation may reduce IZ INa. PP2A1 (625 munits/ml, internal solution) caused a reduction of INa in IZs (–2.77±0.8; n=4), while it showed little effect in NZs [–18.4±6 pA/pF (n=5)].
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4. Discussion |
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TopAbstract1. Introduction2. Methods3. Results4. DiscussionReferences |
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β adrenergic stimulation has been shown to increase Na+ current amplitude by at least two different mechanisms; a protein kinase A (PKA)-dependent (indirect) and a PKA-independent or direct mechanism.
For the PKA independent mechanism, it is thought that isoproterenol binding to the β receptor results in the activation of Gs signaling molecules, which in turn lead to the recruitment of Na+ channels to "active" sarcolemmal positions [15,16]. The PKA-dependent mechanism of β adrenergic stimulation regulates functional expression of INa by phosphorylation Ser526 and Ser529 residues of the I–II linker [12,13,17]. Furthermore, an adrenergic-induced shift in voltage dependence of channel activation and inactivation to more hyperpolarized potentials has been described for INa of native cells from normal hearts [18,19] and INa of recombinant channels [8]. In oocyte experiments, it has been shown that phosphorylation of the cardiac Na+ channel protein facilitates the export of such from the ER to the cell surface [17].
In this report, we show that the established PKA effect on density/kinetics of INa in native cells from normal ventricle exists in NZs, canine epicardial cells from noninfarcted hearts. However, unlike data from previous experiments [8], the observed effects of the PKA cocktail to augment INa in NZs is only partially inhibited by the trafficking inhibitor chloroquine. Thus, in normal ventricular cells, activation of PKA modulates function of Na+ channels by at least two mechanisms, one of which (
10% of the increase) depends on intracellular vesicular traffic.
Because we have suggested that the altered INa of IZs contributes to reduced excitability and postrepolarization of the epicardial border zone of the 5-day infarcted heart [3,4], we sought to promote PKA phosphorylation of IZ INa to restore INa function in the remodeled myocyte. Similar to NZs, we found that the PKA activator cocktail increased IZ INa amplitude as well as shifted the voltage dependence of channel activation and inactivation. Furthermore, we found the PKA activator cocktail to slow the time course of recovery of INa from inactivation as well as to promote closed state inactivation, although under basal conditions, these kinetics parameters are already altered. Importantly, unlike NZs, the PKA activator cocktail only augmented IZ INa by 17%. Thus, while there is some but significant restoration of Na+ currents in IZs with experimental PKA activation, it is significantly muted compared to that seen in NZs. This suggests to us that there may be additional reasons for the decreased INa density in IZs (e.g., loss of transcription, presence of "blocking" particle in pore, etc.). Furthermore, all augmenting effects on INa in IZs were abolished in the presence of the trafficking inhibitor chloroquine. Thus, Na+ channel function can be partially restored in IZs, and the mechanism of this restoration may be due to the acceleration of trafficking of available Na+ channel proteins to the cell membrane. Interestingly, our studies, designed to promote dephosphorylation or phosphorylation of basal Na+ channel proteins of IZs by directly including a specific enzyme inhibitor or a dephosphorylating enzyme in the internal pipette solution, did not further augment the already reduced INa of IZs. In fact, the results of our PP2A1 experiments suggest that in IZs, Na+ channel proteins in the basal state are already phosphorylated.
4.1 Implications of findings
Our studies were not designed to test the effects of potent PKA stimulation on the reentrant tachycardias that can occur in the EBZ of the 5-day infarcted heart. Rather, we have determined here the experimental effects of potent PKA stimulation of the remodeled Na+ channels of the cells that form the substrate for these arrhythmias. Thus, we can only speculate as to whether PKA stimulation would be antiarrhythmic or proarrhythmic in this setting. For example, while PKA stimulation increased INa in IZs, and this may restore excitability, our studies were completed using nonphysiologic conditions, etc. It may be that in situ IZs, which rest near –85 mV, may actually show reduced availability with PKA stimulation due to the observed altered availability curves. A reduction in excitability may further exacerbate conditions for reentry in this model. Alternatively, potent PKA stimulation of IZs and surrounding NZs may reduce the electrical dispersion of these myocytes in situ, because PKA stimulation seemed to eliminate, or ameliorate at least, the differences in the rates of loss and recovery of availability in the two cell types.
4.2 Study limitations
By experimental design, our experiments were completed at a reduced temperature and extracellular sodium. Under more physiologic conditions, our PKA findings may differ. Furthermore, we have not measured the effects of the PKA cocktail on the late Na current in these cells due to the choice of our recording conditions. It may be that the effects of the PKA activator cocktail will differ from its effects noted here. Finally, as in any single-cell study, we have selected cells from both the NZ and IZ preparations for study, and care must be taken when extrapolating to all cells that have survived in the infarcted heart. Nevertheless, we have shown that partial recovery of the remodeled INa of IZs can be attained with PKA stimulation.
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Acknowledgement |
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Supported by grant HL 66140 from the National Heart Lung and Blood Institute Bethesda, Maryland.
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Notes |
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Time for primary review 25 days
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References |
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