Copyright © 2005, European Society of Cardiology
Dual conductance mode of the TREK-1 channel: A hidden track to mechanoelectric regulation in the heart?
Department of Physiology and Biophysics, Seoul National University College of Medicine, 28 Yonkeun-Dong, Chongno-Ku, Seoul 110-799, South Korea
* Corresponding author. Tel.: +82 2 740 8224; fax: +82 2 763 9667. Email address: earmye{at}snu.ac.kr
Received 23 October 2005; accepted 27 October 2005
See article by Li et al. [12] (pages 86–97) in this issue.
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1. The mechano- and lipid-sensitive background K+ channels in heart |
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Two-pore-domain K+ channels (K2P channels) form a novel class of K+ channels identified in various types of cells. K2P channels display constitutive activity at around the resting membrane potential and are sensitively regulated by various physical and chemical factors [1,2]. Among the members of K2P channels, TREK and TRAAK families respond to the widest variety of stimuli including pH, temperature, unsaturated fatty acids, phospholipids, volatile anesthetics, and membrane stretch [1,2]. The mechanical gating of TREK seems to arise from the direct interaction between the membrane phospholipid and the sensor domain of the channel without involvement of the actin cytoskeleton [3].
The heart undergoes incessant cyclic stretch and sudden changes in volume loading. Such mechanical stress provokes electrical responses termed "mechanoelectric feedback" [4]. To elucidate the mechanism, the role of stretch-activated signal transduction and mechanosensitive nonselective cation channels (NSCMS) have been persistently investigated [5–7]. Besides the more widely recognized NSCMS at the level of whole-cell or tissue experiments, the stretch of local membranes via the patch pipette technique showed mechanosensitive K+ channels in rat atrial myocytes that are also activated by intracellular acidification and arachidonic acids [8,9]. After the cloning of K2P channels, the expression of TREK-1 has been consistently confirmed in cardiac myocytes [10,11]. In this issue of Cardiovascular Research, Li et al. revisited this subject in rat ventricular myocytes and elegantly demonstrated the stretch-activated K+ current not only in the patch membrane but also in the whole-cell recording of myocytes by applying direct axial stretch [12]. The activation of whole-cell K+ current by compressing mechanical stress was previously mentioned by one of the authors, while the exact nature has not been investigated [13].
In addition, Li et al. reported two intriguing findings: the first one is the longitudinal striping pattern of TREK-1 expression in the plasma membrane, which might be advantageous in sensing the elongation of myocytes. Unfortunately, the lack of information about the colocalization or expression of cellular structures (e.g. cytoskeleton) does not allow us further interpretation. The second finding is the dual modes of unitary conductance (132 pS and 41 pS at positive potentials) of TREK-1. Surprisingly, the smaller conductance mode was more frequently observed than the ‘classical’ large conductance mode even in the heterologous expression of TREK-1 [12]. A plausible explanation for not being reported beforehand would be that the conspicuous large-conductance mode of TREK-1 has drawn the main attention by previous researchers, while the small-conductance mode has been regarded as a different kind of endogenous channel. Despite the possible arguing points, the rigorous comparison between native and expression systems demonstrates that actually two conductances arise from a single type of channel genes. Frequently the spontaneous ‘shift’ from one state to another state could occur (see supplementary Fig. 3 of [12]). The random appearance of heterogeneous conductance in the same experimental conditions makes us perplexed as well as amazed. How could it happen at all? In a recent paper by Chapman and VanDongen [14], the frequent appearance of subconductance was observed in Kv2.1 channels composed of a tandem dimer that links two K channel subunits, with different activation thresholds for each monomer. The K2P channels like TREK-1 are believed to be composed of dimers [1,2]. The smaller conductance or the phenomenon of conductance shift might result from the differential gating or regulatory process of each monomer, forming a putative heteromeric pore conformation as in the artificial tandem dimeric Kv2.1 channel [14]. It is widely accepted that the gating process of voltage-gated cationic channel subunits is allosterically coupled, allowing an apparently instantaneous shift from the closed to the open state and vice versa. In contrast to the rapid transition from the subconductance to the full conductance of Kv2.1 [14], however, each conductance mode of TREK-1 appears to be quite stable once it has appeared [12]. Assuming that the model by Chapmann and VanDongen is applied to TREK-1, one might have to suppose that an allosteric coupling of channel subunits would be very weak in TREK-1. Apart from the molecular mechanisms of the dual conductance mode, the paper by Li et al. suggests that we look again at the single channel recordings of the other K2P channels.
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2. Physiological role of TREK-1 in heart |
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Top1. The mechano- and...2. Physiological role of...References |
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In spite of the unequivocal presence of TREK-1, mechanical stimulation of cardiac myocytes consistently demonstrates depolarization of the resting membrane potential [4–6]. Therefore, the mechanoactivation of TREK-1, if it occurs, could oppose the depolarizing influences only in a partial manner. Even so, however, the plausible role of TREK-1 in buffering the depolarizing action of NSCMS in a beating heart would have to be considered not only for a qualitative understanding but also for the quantitative construction of a cardiac simulation model [5].
The multifaceted sensitivity of TREK-1 gets more of our attention in pathophysiological situations. As mentioned above, TREK-1 is not only mechanosensitive but also activated by arachidonic acid and internal acidosis [1,2]. Lowering intracellular pH shifts the pressure-activation relationships of TREK-1 toward positive values and leads to channel opening without membrane stretch [15]. During the process of ischemia, arachidonic acid is increased in the cardiac tissue and diffuses into the cytoplasm, which decreases the intracellular pH [16]. Thus, TREK-1 might contribute to the stabilization of the membrane potential of cardiomyocytes under ischemic conditions along with the ATP-sensitive K+ channels.
In neuronal cells where the expression of TREK channels is highly prominent, their activation is supposed to play a role in the protection of the neuronal cell against excessive and deleterious neuronal excitability. Thus, TREK-1 and related channels emerge as potential targets for developing new therapeutic agents [2]. Although TREK-1 knock-out mice do not display an appreciable cardiovascular phenotype under control conditions, ischemic stress in neuronal tissues revealed reduced protective effects [17]. In a similar context, an investigation of ischemic tolerance or adaptation to mechanical load in TREK-1 (–/–) mice might reveal their potential role in the heart. Although the quantitative understanding of the contribution from TREK-1 in vivo has still a long way to go, the present study reminds us that one of the hidden tracks to comprehensive knowledge has alternative paths, both wide and narrow.
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