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Experimental Physiology 89.3 pp 237-242
DOI: 10.1113/expphysiol.2003.027052
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Differential expression of the mechanosensitive potassium channel TREK-1 in epicardial and endocardial myocytes in rat ventricle

Joy H. C. Tan, Weihong Liu and David A. Saint

School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia


   Abstract
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 Abstract
Introduction
 Methods
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 Discussion
 References
 
Mechanoelectric feedback (MEF) is the process by which mechanical forces on the myocardium induce electrical responses. It is thought that MEF is important in controlling the beat to beat force of contraction in the ventricle, in response to fluctuations in load, and it may also play a role in controlling the dispersion of repolarization. The transduction mechanism for MEF is via stretch sensitive ion channels in the surface membrane of myocytes. Two types of stretch sensitive channels have been described; a non-selective cation channel, and a potassium selective channel. TREK-1 is a member of the recently cloned tandem pore potassium channels that has been shown to be mechanosensitive and to be expressed in rat heart. Here we report that the gene expression level of TREK-1, quantified using real-time RT-PCR against glyceraldehyde phosphate dehydrogenase (GAPDH) as a comparator gene, was found to be 0.34 ± 0.14 in endocardial cells compared to 0.02 ± 0.02 in epicardial cells (P < 0.05). To confirm that this is reflected in a different current density, whole cell TREK-1 currents, activated by chloroform, were recorded with patch clamp techniques in epicardial and endocardial cells. TREK-1 current density in epicardial and endocardial cells was 0.21 ± 0.06 pA/pF and 0.8 ± 0.27 pA/pF, respectively (P<= 0.05). We discuss the implications of this differential expression of TREK-1 for controlling action potential repolarization when the myocardium is stretched. We hypothesize that the gene expression of TREK-1 is controlled by the different amounts of stretch experienced by muscle cells across the ventricular wall.

(Received 18 December 2003; accepted after revision 9 January 2004; first published online 17 February 2004)
Corresponding author D. A. Saint: School of Molecular and Biomedical Sciences, University of Adelaide, Adelaide, SA 5005, Australia. Email: david.saint{at}adelaide.edu.au


   Introduction
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 Abstract
 Introduction
Methods
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It is thought that a common arrhythmogenic stimulus is temporal and spatial dispersion of repolarization of the ventricular action potential leading to local re-entrant circuits, and hence triggering after-depolarizations (e.g. Volders et al. 2000). Dispersion of repolarization is normally minimized by the different durations of epicardial and endocardial action potentials, the briefer action potentials in endocardial cells tending to synchronize repolarization in endocardial cells with that in epicardial cells, despite their later activation (Cowan et al. 1988).

This difference in action potential duration is largely a result of epicardial and endocardial cells having different gene expression levels of potassium channels. For example, voltage-activated potassium channels such as Kv 4.2 and Kv LQT1 have been found to be expressed differentially across the ventricular wall (Dixon et al. 1996; Pereon et al. 2000), with the expression of Kv 4.2 being more than eight times higher in epicardial muscle cells compared to papillary muscle cells (Dixon & McKinnon, 1994).

The observation that there are stretch sensitive, or ‘mechanosensitive’, ion channels in myocytes, at least one type being a potassium channel (Hu & Sachs, 1997), raises the possibility that mechanical forces on the myocardium may also influence action potential repolarization. Indeed, there is direct evidence for this in animals and humans (e.g. Greve et al. 2001; Ravelli et al. 1994).

Hence, a logical extension of the idea that action potential repolarization is differentially controlled in epicardial and endocardial cells, and that mechanosensitive potassium channels can influence repolarization, is the notion that mechanosensitive potassium channels may also be differentially expressed in epicardial and endocardial cells, in a way analogous to the to expression of Kv4.2 and other channels.

Although mechanosensitive potassium channels have been recorded in myocytes and other cells for some time (Kim, 1992; Sackin, 1995), the identity of these channels has been uncertain. The recent cloning of the tandem pore family of potassium channels (Fink et al. 1996) has to a large extent resolved this. All members of this gene family are potassium channels (Lesage & Lazdunski, 2000), although their properties can vary quite widely. In contrast to the shaker-type potassium channel family, none are strongly voltage dependent. At least one member of the family, TREK-1, has been found to be highly expressed in cardiac tissues of rats and, when expressed in heterologous systems, forms a mechanosensitive potassium channel with the same characteristics as a mechanosensitive potassium channel recorded in isolated myocytes using patch clamp techniques (Aimond et al. 2000; Tan et al. 2002).

However, the link between mRNA expression level and the level of the corresponding (and functional) protein can often be less than obvious; for example, in rat cardiomyocytes, Kv1.4 protein is very inefficiently expressed, although there is abundant mRNA transcription (Barry et al. 1995). Hence, we also examined the level of expression of functional TREK-1 channels in isolated myocytes by recording whole cell currents induced by chloroform. [Among the potassium channels present in the heart, TREK-1 alone is activated by chloroform (Terrenoire et al. 2001)]. In parallel with the difference in mRNA expression, we find a significantly larger whole cell current in myocytes isolated from the endocardium compared to the epicardium.

It seems likely that the heterogeneity in the expression of TREK-1 will contribute to the heterogenous repolarization occurring in different layers of the ventricular wall, which are known to experience different stresses during stretch. We hypothesize that this heterogeneity is part of the ‘tensegrity’ role for mechanosensitive channels proposed, for example, by Laboratory (1999).


   Methods
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 Introduction
 Methods
Results
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All animals care arrangements and experimental techniques used in this study were approved by the University of Adelaide Animal Ethics Committee.

Preparation of epicardial and endocardial myocytes

Adult rat heart cells were prepared as previously described (Saint et al. 1992). Briefly, adult Sprague-Dawley rats were anaesthetized with 100% CO2 inhalation and killed by exsanguination. Hearts were removed and perfused with Tyrode's solution with added collagenase to digest the extracellular matrix. When digestion of the heart was complete, pieces of left epicardial tissue and left endocardial tissue were dissected free (no more than 1 mm from either ventricular surface) and cells dissociated by trituration. Myocyte preparations were filtered through 80 µM nylon mesh, and checked for viability microscopically. The success in separating epicardial and endocardial cells was confirmed for each experiment by taking an aliquot of the cells and measuring the size of the transient outward current, Ito, which is known to be expressed almost exclusively in epicardial cells (Honen & Saint, 2002).

Real time PCR techniques

Total RNA was extracted from pure epicardial and endocardial myocyte preparations from six adult Sprague-Dawley rats using TRIzol Reagent (Life Technologies, Inc, Frederick, Maryland, USA). Real-time PCR was performed for TREK-1 (genebank accession number U73488 [GenBank] ) and a rat house-keeping gene, GAPDH (genebank accession number M32599 [GenBank] ), using cDNAs corresponding to 200 ng total RNA synthesized from left ventricular epicardial and endocardial cells. The gene specific primers were: TREK-1, forward 5'-TTTGGCTTTCTACTGG CTGGGG-3', reverse 5'-TCGTCTTCTTAGAGATCACCG-3'; GAPDH, forward 5'-ATGTTCCA GTATGACTCCACTCACG-3', reverse 5'-GAAGACACCAGTAGACTCC ACGACA-3'. All primers were purchased from GeneSet (GeneSet Pacific Pty. Ltd, Australia). SYBR Green real-time PCR assays were performed on the cDNA samples in 96-well optical plates on an ABI Prism 5700 Sequence Detection System (PE Applied Biosystems, Foster City, CA). GAPDH assays were run parallel to each different sample. For each 25 µl SYBR Green PCR reaction, 2.5 µl cDNA, 1.5 µl sense primer (5 µM), 1.5 µl antisense primer (5 µM), 12.5 µl SYBR Green PCR Master Mix (PE Applied Biosystems, Foster City, CA) and 7 µl PCR-grade water were mixed together. The parameters for a two-step PCR were 95°C for 10 min, 1 cycle, then 60°C for 1 min, 95°C for 15 s, 40 cycles. Before quantification of real-time PCR data, the specificity of the amplified products was examined by both running the products in 3% agarose gel and dissociation curve analysis.

For comparison of gene expression levels, all quantification were normalized to endogenous GAPDH expression level to account for variability in the initial concentration and the quality of the total RNA in the conversion efficiency of the reverse transcriptase reaction. The amplification efficiency-based method was used for quantification and normalization as developed by Liu & Saint (2002).

Patch-clamp techniques

All electrophysiological recordings were acquired at room temperature of 22–24°C, using an Axopatch 200 A patch-clamp amplifier (Axon Instruments, Union City, CA, USA). Electrodes were fashioned from borosilicate glass (Harvard apparatus PG150T-7.5) and filled with pipette solution containing (mM): KF, 120; MgCl2, 6.8; EGTA, 10; HEPES, 20. Typically, pipettes had resistances of 1–2 M{Omega}. The extracellular solution during recording contained (mM): Choline.Cl, 143.5; HEPES, 10; NaH2PO4, 1.2; KCl, 4; MgCl2, 1.2. To measure TREK-1 currents, other ionic currents were blocked by adding: 2 mM CoCl2; 5 mM TEA and 10 µM glybenclamide to the bath solution. Note that we have previously shown that TREK is activated by intracellular ATP (Tan et al. 2002). In order to avoid ‘tonic’ activation of TREK currents, ATP was omitted from the intracellular solution. Data traces were acquired at a repetition interval of 10 s using proprietary software (written by M. Smith, John Curtin School of Medical Research, Australian National University, Canberra, Australia). The holding potential was kept at –50 mV. A voltage step to –70 mV was applied for 400 ms followed by a voltage step to –30 mV for 400 ms. The difference in the current at these two potentials was measured, and the increase in this difference in the presence of chloroform taken as an index of current passing through TREK channels. Whole-cell recordings were analysed using proprietary software (written by M. Smith, John Curtin School of Medical Research).

Statistics.  mRNA expression level and TREK-1 whole-cell currents for epicardial and endocardial cells of the left ventricle were compared using Student's t test. P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
mRNA expression of TREK-1 in epicardial and endocardial cells

Figure 1A and B shows the SYBR Green real-time PCR kinetic data traces of TREK-1 channel genes and the corresponding dissociation curves that checks for primer-dimer formation in the reaction. Dissociation curve analysis showed that the melting temperature for the genes was more than 75°C, indicating no primer-dimer formation (Fig. 1B). The specificity of the amplification was also examined by running the product in 3% agarose gel, which revealed a single band consistent with the predicted size for TREK-1. It appeared from the gel that there was a higher expression of the channel in the endocardial cells compared to epicardial cells. Using the amplification efficiency-based method developed by Liu & Saint (2002) for quantification and normalization of real-time PCR products, the expression of TREK-1 (using GAPDH as a reference) was found to be significantly higher in the endocardial cells compared to the epicardial cells, i.e. 0.34 ± 0.14 and 0.02 ± 0.02, respectively (P < 0.05; Fig. 1D).



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  		Figure 1.  mRNA expression of TREK-1 in the epicardial and endocardial cells of the left ventricles of the rat
A shows the SYBR Green real-time PCR kinetic data traces for the genes of TREK-1 and GAPDH; B shows the corresponding dissociation curves of the real-time PCR products. Dissociation curve analysis shows that the melting temperature for the genes was more than 75°C, indicating no primer-dimer formation. C shows a rough estimate of mRNA expression of TREK-1 in the epicardial and endocardial myocytes. There appears to be a higher mRNA expression of TREK-1 in the endocardial cells. D, using real-time PCR techniques, the expression of TREK-1 relative to GAPDH was found to be higher in endocardial cells (0.34 ± 0.14) compared to epicardial cells (0.02 ± 0.02) (n= 6).

 
TREK-1 whole-cell currents in the epicardial and endocardial cells

The upper diagram in Fig. 2A shows the voltage-step protocol used. Small voltage steps were applied to prevent activation of voltage-gated potassium channels. The resultant whole-cell current for control solution and bath solution containing 0.04% chloroform is shown in the lower diagram. Figure 2B shows the difference between the whole-cell current of an endocardial cell at –30 mV and at –70 mV plotted before and during addition of chloroform as well as during washout of chloroform. There is a notable increase in the whole-cell current with chloroform in the bath. This current is attributed to the opening of TREK-1 channels. The graph in Fig. 2C shows current normalized for the cell capacitance for epicardial (0.2 ± 0.06 pA/pF) and endocardial (0.8 ± 0.27 pA/pF) cells. This difference in current density was highly significant (P < 0.05).



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  		Figure 2.  Whole-cell currents induced by chloroform
The upper diagram in A shows the voltage protocol used to observe whole-cell TREK-1 currents. The holding potential was –50 mV. A –70 mV pulse was applied for 400 ms followed by a 400 ms current pulse to –30 mV. This current step was repeated every 10 s. The lower diagram in A shows the resultant whole-cell current using this voltage-step protocol for both the control solution and the bath solution containing 0.04% chloroform (recontrol current is indistinguishable from control current). B, the difference in the whole-cell current at –30 mV and –70 mV before and the effect of chloroform. Data shown in A and B are obtained from different cells. C, normalized current (whole cell current divided by the cell's capacitance) for both the epi- and endocardial myocytes of left ventricles for six rats. The mean current for endocardial and epicardial cells are 0.8 ± 0.27 pA/pF and 0.21 ± 0.06 pA/pF, respectively. There is a significant difference in the size of TREK-1 whole-cell current between the epi- and endocardial cells (P<= 0.05).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of this study demonstrate that there is a heterogenous distribution of TREK-1 channels between epicardial and endocardial cells in the left ventricle of rat heart. Other potassium channels have also been shown to have a heterogeneous distribution (Casis et al. 1998), although at least one study, using Northern blot techniques, has shown that TBAK-1 and TASK-1, non-mechanosensitive members of the tandem pore potassium channels, are not differentially expressed in epicardial and endocardial cells (Kim et al. 1999). Hence, there may be a special role for mechanosensitive channels potassium channels in the heart.

The idea that mechanical forces on the myocardium can produce electrical responses (a process known as mechanoelectric feedback, MEF) is not novel (e.g. Bainbridge, 1915) although the physiological function of this response is not clear. Lab has suggested that MEF plays a role in reducing dispersion of action potential repolarization in areas of the myocardium where action potential conduction velocity may be slowed (Lab, 1999). A full appreciation of the role of MEF has been elusive, however, in the absence of good quantitative models of the magnitude of the response in different areas of the myocardium. There is no doubt that the degree of stretch experienced by the muscle fibres in different areas of the myocardium can be very different, being influenced by cardiac geometry and fibre orientation (Vetter & McCulloch, 1998; Arts et al. 2001), which will certainly influence the degree of MEF produced at cellular scale. Indeed, Dutetre and collegues reported in 1972 that mechanically induced changes in action potential duration were dissimilar in different parts of the intact left ventricle (Dutetre et al. 1972). Similarly, Takagi et al. (1999) reported that epicardial monophasic action potential duration was shortened while endocardial monophasic action potential duration remained unaltered when canine left ventricles were subjected to stretch. However, it is not possible to say whether this is due to the different stresses experienced by different areas within the myocardium, or to a different ‘gain’ of MEF in those areas, due to, for example, different current densities of stretch induced currents in the cells. Our results here suggest that the gain of MEF may be different in different areas of the heart, due to different levels of gene expression of mechanosensitive channels.

This observation raises two questions.

1 What is it that controls the level of gene expression? It is known that stretch itself can modulate the level of expression of a number of genes (Komuro & Yazaki, 1993; Yamazaki et al. 1998; Sadoshima & Izumo, 1997; Omens, 1998; Cheng et al. 1995). These changes may be a consequence of the presence of mechanosensitive ion channels (Sadoshima et al. 1992). For example, chronic haemodynamic stress that leads to congestive heart failure (CHF) and the accompanying cellular hypertrophy may be initiated by stretch- or swelling-activated currents (Vandenberg et al. 1996; Clemo & Baumgarten, 1997). Modulation of the gene expression of a mechanosensitive channel such as TREK-1 by stretch itself would form an elegant feedback mechanism.
2 What are the implications of the different gain of MEF in different parts of the heart? As noted above, a strong arrhythmogenic stimulus is provided by excessive dispersion of repolarization. Laboratory (1999) has speculated that MEF contributes to reduction in dispersion of repolarization in the face of local perturbations of action potential propagation.

We hypothesise that MEF is modulated at a cellular level to minimise dispersion of repolarisation when the myocardium is stretched. As a consequence, any perturbation of the mechanical synchrony either by electrical changes (e.g. propagation velocity) or mechanical changes (e.g. valve incompetence or stenosis) will alter the gene expression of mechanosensitive channels so that dispersion is minimised under the new conditions. Following on from this it seems possible that the propensity to arrhythmogenesis in some human disease states such as cardiac hypertrophy may be due in some measure to altered mechanoelectric feedback due to alteration in gene expression of mechanosensitive channels. While the evidence is sparse that TREK is expressed in human heart, there is no doubt that mechanoelectric feedback of the type expected from the presence of TREK, or a similar channel is present in both human atria (Ravelli et al. 1994) and ventricles (Taggart et al. 1992). Our demonstration here that expression in different parts of the heart can be different may be why it has been difficult to demonstrate the expression of TREK in human heart. Alternatively, it may be that the role played by TREK in rat heart is taken by another member of the two pore channel family in humans, or, somewhat more speculatively, a different type of mechanosensitive channel.


   Footnotes
 
J. H. C. Tan and W. Liu contributed equally to this work.


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 Introduction
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 Discussion
 References
 
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