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Cardiovascular Research 2003 59(1):37-45; doi:10.1016/S0008-6363(03)00357-2
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Copyright © 2003, European Society of Cardiology

Increased open probability of single cardiac L-type calcium channels in patients with chronic atrial fibrillation

Role of phosphatase 2A

Gunnar Kleina,*, Frank Schrödera, David Voglera, Arnd Schaefera, Axel Haverichb, Bernhard Schieffera, Thomas Kortea and Helmut Drexlera

aDepartment of Cardiovascular Medicine, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
bDepartment of Cardiovascular Surgery, Hannover Medical School, Hannover, Germany

gunnarklein{at}yahoo.de

* Corresponding author. Tel.: +49-511-532-6524; fax: +49-511-532-8475.

Received 1 December 2002; accepted 23 March 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The L-type calcium channel (LCC) plays a crucial role in the electrical remodeling of atrial fibrillation (AF). AF is associated with reduction of L-type calcium current density, due to a transcriptional downregulation of the pore forming alpha1c-subunit of LCC. However, it is unclear, whether this current reduction is related to a decrease in channel number or to alterations in channel function. Hence, we performed a single LCC analysis to assess channel gating and function in human AF. Methods and results: We used the cell-attached patch-clamp technique in isolated atrial human cardiomyocytes of 25 patients with sinus rhythm (SR) and 15 patients with chronic AF. Protein expression of the pore-forming {alpha}1c-subunit of LCC was reduced by 40% in AF. Single channel peak average current was 1.7-fold higher in AF than in SR, due to a 3.1-fold higher open probability of LCC. Since phosphatase 2A (PP2A) is known to preferentially reduce LCC open probability via channel dephosphorylation, we assessed whether PP2A expression or activity is reduced in AF. Okadaic acid, an inhibitor of phosphatases, increased channel open probability in SR, but not in AF. However, Western blot analysis of atrial homogenates of the same patient population revealed unchanged expression of PP2A. Conclusions: Human AF is characterized by increased single LCC activity, due to an increase of channel open probability. The blunted effect of PP2A on LCC as shown by single channel analysis may be related to a reduction of cytosolic PP2A activity or impaired local interaction between PP2A and LCC in AF.

KEYWORDS Arrhythmia (mechanisms); Ca-channel; Single channel currents


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical cardiology. Once AF has developed electrophysiological remodeling is responsible for the perpetuation of AF [1]. Electrophysiological studies revealed that the L -type calcium channel plays a crucial role in atrial remodeling [2,3]. Whole-cell voltage-clamp studies in canine atrial cardiomyocytes showed that atrial tachycardia leads to a substantial reduction in L-type calcium current density [4]. Whole-cell voltage-clamp studies in human atrial cardiomyocytes showed a 60% reduction of L-type calcium current in AF [5]. It appears that this is attributable to a transcriptional downregulation of the pore forming {alpha}1c-subunit of the L-type calcium channel [6–8]. Thereby action potential duration and atrial refractoriness are reduced, subsequently predisposing to atrial re-entry and contributing to the perpetuation of AF [9].

However, data concerning transcriptional and translational downregulation of {alpha}1c-subunit of the L-type calcium channel are inconclusive. In animal models of AF mRNA was reduced [6,10]. A reduced mRNA content was also shown in humans with AF in some studies [8,11], but were not confirmed by others [12]. Similarly, conflicting results exist concerning protein levels of the {alpha}1c-subunit of the L-type calcium channel in human AF with decreased levels in one [11] and unchanged levels in another study [13]. Therefore evaluation of single channel function might be all the more interesting, because whole-cell current is determined by the product of both the number of functional channels and their individual properties, i.e. single channel current amplitude, open probability and availability. However, data concerning single channel function assessed by single channel analysis in AF are not yet available.

As compared to whole-cell current measurements analysis of single L-type calcium channel gating provides several advantages and potential mechanistic insight. First, the pattern of single channel gating is characteristic for different second messengers influencing single channel activity such as kinases and phosphatases. Second, in contrast to whole-cell current measurements we studied intact atrial cardiomyocytes, avoiding loss of important intracellular second messengers by diffusion into the patch pipette. Therefore, for the first time our analysis focuses on single L-type calcium channel gating in human atrial cardiomyocytes of patients with AF. We investigated, whether (i) qualitative changes occur in single L-type calcium channel gating in AF and whether (ii) the underlying molecular mechanism for these differences in channel gating can be elucidated.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Patient selection
The investigation conforms with the principles outlined in the Declaration of Helsinki and was approved by a local ethics committee. All patients gave written informed consent.

Right atrial appendages were obtained from 40 patients undergoing cardiac surgery (aortocoronary bypass, mitral valve replacement or aortic valve replacement). Exclusion criteria were ejection fraction below 50% and patients on calcium antagonists. Patients with latent or manifest hyperthyroidism in their history were excluded. Patients either had sinus rhythm or chronic persistent atrial fibrillation for a duration of at least 6 months.

2.2 Cell isolation
Tissue samples were placed in preoxygenated solution A of 4°C (composed of 100 mM NaCl, 10 mM KCl, 5 mM MgSO4, 20 mM dextrose, 50 mM taurine, and 5 mM MOPS (pH 7.4)). The samples were dissected into 1x1 mm pieces at room temperature. The remaining tissue was deep-frozen and stored at –80°C for Western blot analysis. Samples were digested in 10 ml of solution A in the presence of 310 U/ml collagenase I, 0.5 mg/ml protease XXIV, and 10 mg/ml bovine serum albumin (BSA) at 37°C for 40 min under continuous shaking. After removal of supernatant, tissue samples were incubated again with solution A in the presence of 103 U/ml collagenase I and 1 mg/ml BSA for 60 min at 37°C. After removal of the supernatant the cells were resuspended in solution B (50 mM potassium glutamate, 40 mM KCl, 20 mM KH2PO4, 20 mM taurine, 20 mM KOH, 3 mM MgCl2, 10 mM HEPES, 5 mM EGTA, and 10 mM dextrose (pH 7.4)).

2.3 Single channel measurement and analyses
Cell suspension was preincubated at room temperature for 30 to 60 min with 10 µM BAPTA-AM (1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetra-(acetoxymethyl)-ester. Cells were placed in disposable perfusion chambers containing 1–2 ml of bath solution (120 mM potassium glutamate, 25 mM KCl, 2 mM MgCl2, 10 mM HEPES, 2 mM EGTA, 1 mM CaCl2, 1 mM Na–ATP, 10 mM dextrose, pH 7.4 with NaOH). Single channel recordings were performed in the cell-attached configuration. In brief, pipettes (borosilicate glass, 5–7 M{Omega}) contained 70 mM BaCl2, 110 mM sucrose, 10 mM HEPES (pH 7.4 with TEA-OH). Barium currents were elicited for 150 ms at 1.66 Hz by depolarizing test pulses with command pulses from –100 mV to +20 mV. Recordings were sampled at 10 kHz and filtered at 2 kHz (–3 dB, 4-pole Bessel) using an Axopatch 200 B amplifier (Axon Instruments, Foster City, CA, USA). The pClamp software (version 6.0, Axon Instruments) was used for data acquisition and analysis of openings and closures. L-type calcium channels were usually found in one out of 5–10 patches. Single L-type calcium channels were characterized and identified by their conductance. For this purpose depolarizing pulses from a holding potential of –100 mV were elicited to test potentials between 0 and +30 mV. By plotting the amplitude of fully resolved openings against the test potential for every single experiment, we calculated channel conductance.

Analysis was performed as previously described [14]. Linear leak and capacity currents were digitally subtracted using averaged currents of non-active sweeps. The availability (fraction of sweeps containing at least one channel opening, e.g., fraction of active sweeps per total number of test pulses), open probability (i.e., fractional occupancy of the open state during active sweeps), and the peak ensemble average current were corrected by the number of channels in the patch (n). Peak current is the maximum of the ensemble average current from one single channel. In case of double- or triple-channel patches, n was derived from the maximum current amplitude observed divided by the unitary current amplitude. Peak current was normalized by division through n. Availability was corrected by the square root method: (1-availabilitycorrected) is the nth root of (1-availabilityuncorrected). Open probability was calculated on the basis of the corrected number of active sweeps, i.e., total open time (in ms) within all sweeps of the ensemble, divided by (150 msxnxavailabilitycorrxnumber of test pulses). Openings and closures were identified by the half -height criterion. In case of single channels, mean open times were calculated from the total open time of the channel divided by the sum of the number of closures and the number of active sweeps. Mean close time was calculated from total close time divided by the number of closures.

2.4 Western blots
Equally loaded total cell lysates (50 µg/lane) of each sample were fractionated on 10% sodium dodecyl sulfate (SDS)–polyacrylamide gels. The proteins were transferred electrophoretically to a polyvinylidene difluoride membrane. Equal transfer was verified by staining with Ponceau Red. Membranes were blocked using 5% BSA in TTBS (20 mM Tris, 150 mM NaCl, 0.05% Tween 20, pH 6.8) for 1 h. Membranes were then incubated overnight in primary antibody solutions in 5% BSA in TTBS at 4°C. After washing three times in TTBS membranes were incubated with horseradish peroxidase conjugated anti-mouse IgG-antibody (Amersham) in 5% BSA in TTBS for 1 h at room temperature. Then the membranes were washed three times in TTBS before performing antibody detection by chemiluminescence. The density of bands was quantified by use of a scanner and Quantity One software (BioRad). For this series of experiments samples were taken from six patients of each group (SR and AF) included in the single channel analysis.

2.5 Drugs
All drugs were purchased from Sigma except okadaic acid (NH 4 salt from Calbiochem, 10–4 M stock in DMSO) and collagenase I (Worthington). Primary antibodies against phosphatase 1 and 2A were purchased from Transduction Laboratories, Lexington, USA. Primary antibody against {alpha}1c-subunit of L-type calcium channels was purchased from Alomone Laboratories.

2.6 Statistics
Data are presented as mean±S.E.M. Differences were evaluated by t-test analysis (P<0.05).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Patient characteristics
The baseline characteristics of patients with SR (n = 25) and AF (n = 15) are compiled in Table 1. Patients with AF were significantly older and more often underwent mitral valve replacement and had higher left atrial diameter. Mean right atrial pressure and ejection fraction was not significantly different. Patients with AF more often took ACE-inhibitors and glycosides.


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  		Table 1 Baseline patient characteristics

 
3.2 Protein expression of L-type calcium channels in AF
As previously shown by others [11] Western blot analysis revealed a 40% reduction of the pore forming {alpha}1c-subunit of the L-type calcium channel in patients with chronic AF (Fig. 1)


Figure 1
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  		Fig. 1 (A) Western blots incubated with L-type calcium channel antibody ({alpha}1c-subunit). Representative blots of two patients with AF and two patients with SR. AF indicates atrial fibrillation, SR indicates sinus rhythm, marker indicates 200 kD. (B) Summary of results of L-type calcium channel expression (six patients with SR (clear column); six patients with AF (filled column); *P<0.05).

 
3.3 Baseline characteristics of L-type calcium channel gating in AF
Single L-type calcium channels were characterized by their conductance. Depolarizing pulses from a holding potential of –100 mV were elicited to test potentials between 0 and +30 mV. Channel availability and open probability increased with voltage. We determined the single channel conductance plotting the amplitude of fully resolved openings against the test potential for every single experiment. The mean of slopes of the linear relationship of eight (SR) resp. seven (AF) experiments was 18.6±1.7 pS in SR and 19.3±2.1 pS in AF (P>0.05). These results are in accordance with data recently obtained from human atrial cardiomyocytes [15].

Peak current was 1.7-fold higher in AF than in SR (Table 2), due to a 3.1-fold higher open probability of L-type calcium channels in AF. There was no difference in availability between both groups. Higher open probability in AF was attributable to a significantly shortened mean first latency and mean close time (Fig. 2). Thus, L-type calcium channels in AF open earlier and close times between channel openings are shorter.


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  		Table 2 Baseline characteristic of L-type calcium channel gating in SR and AF

 

Figure 2
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  		Fig. 2 Representative single channel recording from a patient with SR (left) and a patient with AF (right). Top trace: voltage protocol. Middle traces: consecutive sweeps. Bottom traces: ensemble average current. Scale bars indicate 15 ms and 2 pA (unitary current), 15 fA (ensemble average current).

 
The differences in open probability remained significant, even when excluding all patients taking glycosides and/or ACE-inhibitors (data not shown).

3.4 Effect of β-adrenergic inhibition/stimulation on L-type calcium channel gating in AF
β-adrenoceptor stimulation leads to activation of adenylate cyclase, generation of cAMP and activation of protein kinase A (PKA). PKA-dependent phosphorylation of L-type calcium channel increases calcium current due to elevation of availability and open probability on single channel level [16,17]. Thus, our results could in part have been influenced by treatment with β-blockers. Hence, we compared subgroups of patients with SR and AF, with and without β-blockers. Table 3 shows that there was no significant influence of β-blocker treatment on L-type calcium channel gating in our study. However, there was a non-significant trend that β-blocker treatment reduced peak current in AF due to a reduction of channel availability and open probability. We did not observe this trend in patients with SR. Moreover, we studied the effect of β-adrenergic stimulation on single L-type calcium channel activity in AF and SR. Membrane permeable PKA activator 8Br-cAMP (10–3M) increased peak current in AF and SR (Fig. 3; baseline: AF vs. SR: 28.78±5.52 fA vs. 19.18±5.25 fA, P<0.05, after 8Br-cAMP: 55.78±8.12 fA in AF vs. 41.55±9.12 fA in SR, P>0.05). In SR this was due to an increase in both, availability and open probability, whereas in AF only availability increased (Fig. 3; baseline availability in AF vs. SR: 34.67± 7.55% vs. 38.73±5.71%, P>0.05; availability after 8Br-cAMP: 46.22±7.39% vs. 58.09±6.87%, P>0.05; baseline open probability in AF vs. SR: 13.44±3.83% vs. 4.82±1.32%, P<0.05; open probability after 8Br-cAMP: 14.11±1.95% vs. 9.25±2.11%, P>0.05).


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  		Table 3 Influence of β-blocker treatment on L-type calcium channel gating

 

Figure 3
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  		Fig. 3 Summary of results from single channel recordings obtained from patients with SR (left) and patients with AF (right). (A–C) Shows the effect of 8Br-cAMP on peak current (A), availability (B) and open probability (C) in SR. After obtaining control registrations (clear columns), 8Br-cAMP (10–3M) was added to the bath solution (filled columns). Data are presented as mean±S.E.M. (nine recordings from five patients). (D–F) Shows the effect of 8Br-cAMP on peak current (D), availability (E) and open probability (F) in AF. After obtaining control registrations (clear columns), 8Br-cAMP (10–3M) was added to the bath solution (filled columns). Data are presented as mean±S.E.M. (nine recordings from six patients). *P<0.05.

 
3.5 Effect of phosphatase inhibitor okadaic acid on L-type calcium channel gating in AF
Increased baseline open probability in AF, which could not be increased by β-adrenergic stimulation and appears to be at its maximum indicates higher baseline phosphorylation state of L-type calcium channels in AF. The pattern of single channel gating excludes contribution of PKA. Apart from kinases higher phosphorylation state of channels can also result from reduced dephosphorylation.

Channel dephosphorylation is regulated by phosphatases, such as phosphatase 1 and 2A. These phosphatases have different effects on single channel gating [18,19]. By dephosphorylation phosphatase 1 preferentially reduces availability, whereas phosphatase 2A preferentially reduces open probability. Thus, higher open probability of L-type calcium channels in AF could be due to reduced influence of phosphatase 2A on L-type calcium channel. Therefore we used okadaic acid as an inhibitor of phosphatase 1 and 2A. Supporting our hypothesis okadaic acid (10–6 M) was able to increase open probability in SR to the level of open probability in AF without okadaic acid (Table 4). In contrast okadaic acid had no effect on open probability in AF. However, availability, known to be regulated by phosphatase 1, increased in both groups, indicating that there is no difference in phosphatase 1 (Fig. 4).


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  		Table 4 Effect of okadaic acid on single L-type calcium channel gating

 

Figure 4
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  		Fig. 4 Representative single channel recording from a patient with SR (A, left) and a patient with AF (B, right). After obtaining control registrations (left side of Fig. 3A and B) okadaic acid (10–6 M) was added to the bath solution (right side of Fig. 3A and B). Top trace: voltage protocol: 150 ms depolarization from –100 mV to +20 mV. Middle traces: consecutive sweeps. Bottom traces: ensemble average current. Scale bars indicate 30 ms and 4 pA (unitary current), 25 fA (ensemble average current).

 
3.6 Protein expression of phosphatase 1 and 2A in atrial fibrillation
To examine if the reduced influence of phosphatase 2A in AF is attributable to decreased protein expression of phosphatases we performed Western blot analyses of lysates from atrial tissue samples (n = 6 in SR and n = 6 in AF) included in single channel analysis. There was no significant difference in phosphatase 1 or 2A expression in patients with sinus rhythm or atrial fibrillation (Fig. 5).


Figure 5
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  		Fig. 5 Western blots incubated with phosphatase 1 (A) and phosphatase 2A (B) antibody. Representative blots of four patients with AF and four patients with SR. AF indicates atrial fibrillation, SR indicates sinus rhythm, marker indicates 36 kD.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study shows, that in human AF single L-type calcium channel activity is increased due to elevated channel open probability. The pattern of single channel gating and the lack of increase in open probability after inhibition of phosphatases by okadaic acid indicate an impaired influence of phosphatase 2A on L-type calcium channels in AF.

Reduced L-type calcium current in AF has been explained by transcriptional downregulation of mRNA of {alpha}1c -subunits of the L-type calcium channel [6,8,10,11] although some studies did not show a significant change in mRNA or protein expression of the pore forming unit of the L-type calcium channel in human AF [12,13]. It must be emphasized, however, that none of the previous investigations, in animals or humans, addressed the question at the single channel level. This is all the more interesting, since a reduction of whole-cell calcium current in AF could also be explained by altered single channel function.

However, we do not show a reduction, as we would have expected but a three-fold increase of L-type calcium channel activity in patients with AF. Furthermore we show a 40% reduction of channel protein expression in AF. At first glance this should not result in decreased whole-cell calcium current in AF. However in Western blot analysis also inactive, internalized channels might contribute to the measured protein amount, the true membrane bound channel number might therefore be much lower than 60%.

As compared to whole-cell current measurements single channel analysis provides the advantage, that the pattern of single channel gating is specific for different second messengers influencing single channel activity such as kinases and phosphatases.

Both, phosphatases 1 and 2A, although acting on the same molecular target have different effects on single channel gating. Phosphatase 1 reduces availability, whereas phosphatase 2 reduces open probability [18,19]. Thus, our single channel data, exclusively showing increase of baseline open probability of L-type calcium channels in AF, are consistent with reduced influence of phosphatase 2A on L-type calcium channels. Accordingly, inhibition of phosphatases by the phosphatase inhibitor okadaic acid had no influence on open probability in AF, whereas open probability in SR was increased. Various mechanisms are likely to be responsible for the impaired influence of phosphatase 2A on cardiac L-type calcium channels in AF. First, protein expression of phosphatase 2A could be reduced. Second, phosphatase activity could be blunted, and third, local interaction of phosphatase 2A with the L-type calcium channel could be impaired. In Western blot analyses of tissue samples of patients with SR and AF we did not observe differences in protein expression of phosphatase 2A. Thus, disturbance of local assembly of phosphatase 2A and membrane bound L-type calcium channel may represent the underlying mechanism, consistent with observations, that immunoprecipitation of the pore-forming {alpha}1c-subunit of brain L-type calcium channels showed co-precipitation of phosphatase 2A [20].

Our study reveals, that electrical remodeling in human AF does not only imply quantitative L-type calcium channel regulation but also altered single channel function. Similarly, in chronic heart failure Schröder et al. [21] and Chen at al. [22] showed higher activity of single L-type calcium channels due to increased phosphorylation state, though mRNA and whole-cell current were unaltered. Thus, in AF increased single L-type calcium channel, channel activity attributable to reduced phosphatase 2A influence is compatible with decreased channel protein expression and in part resembles ventricular electrical remodeling observed in heart failure.

4.1 Potential clinical implications
Atrial refractory period increases substantially within minutes after restoration of SR in patients with AF, due to prolongation of action potential duration [23]. Changes of action potential duration shortly after cardioversion are multifactorial, e.g., dependent on rate, ion currents and drugs. However, this rapid electrophysiological remodeling is unlikely to be due to changes in calcium and potassium channel mRNA or protein levels. In contrast, calcium channel phosphorylation by kinases or decreased channel dephosphorylation by phosphatases, result in rapid increases of calcium current, and therefore may play a crucial role for prolongation of atrial refractory period early after cardioversion. Since our data show that single channel activity is already increased in atrial fibrillation, further increase of open probability and subsequently prolongation of action potential duration appear to be limited. Thus, limitation of increase in open probability of L-type calcium channel could be responsible for immediate recurrence of atrial fibrillation after cardioversion.

In summary, our study shows increased single cardiac L -type calcium channel activity in human AF due to an increase in channel open probability. Simultaneously, we found reduced expression of L-type calcium channels in AF. The pattern of single channel gating and the lack of effect of okadaic acid on open probability in AF indicate an impaired influence of phosphatase 2A on L-type calcium channels, in particular. Since we did not observe reduced expression of phosphatase 2A in AF, it appears that increased single channel activity in AF is either attributable to a reduction of phosphatase 2A activity or impaired local interaction between phosphatase 2A and L-type calcium channels.

Time for primary review 51 days.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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