TREK-2, a New Member of the Mechanosensitive Tandem-pore K+ Channel Family

Bang, Hyoweon; Kim, Yangmi; Kim, Dong‐Hee

doi:10.1074/jbc.m000445200

Cited by 254 publications

(267 citation statements)

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“…TREK1 and TREK2 share ∼65% sequence identity, whereas TREK1 and TRAAK share ∼40% (12)(13)(14). All three subunits are highly expressed throughout the nervous system (12,14), where they display distinct but overlapping distributions (15).…”

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confidence: 99%

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Levitz

Royal

Comoglio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Twik-related K + channel 1 (TREK1), TREK2, and Twik-related arachidonic-acid stimulated K + channel (TRAAK) form the TREK subfamily of two-pore-domain K + (K 2P ) channels. Despite sharing up to 78% sequence homology and overlapping expression profiles in the nervous system, these channels show major differences in their regulation by physiological stimuli. For instance, TREK1 is inhibited by external acidification, whereas TREK2 is activated. Here, we investigated the ability of the members of the TREK subfamily to assemble to form functional heteromeric channels with novel properties. Using single-molecule pull-down (SiMPull) from HEK cell lysate and subunit counting in the plasma membrane of living cells, we show that TREK1, TREK2, and TRAAK readily coassemble. TREK1 and TREK2 can each heterodimerize with TRAAK, but do so less efficiently than with each other. We functionally characterized the heterodimers and found that all combinations form outwardly rectifying potassium-selective channels but with variable voltage sensitivity and pH regulation. TREK1-TREK2 heterodimers show low levels of activity at physiological external pH but, unlike their corresponding homodimers, are activated by both acidic and alkaline conditions. Modeling based on recent crystal structures, along with mutational analysis, suggests that each subunit within a TREK1-TREK2 channel is regulated independently via titratable His. Finally, TREK1/TRAAK heterodimers differ in function from TRAAK homodimers in two critical ways: they are activated by both intracellular acidification and alkalinization and are regulated by the enzyme phospholipase D2. Thus, heterodimerization provides a means for diversifying functionality through an expansion of the channel types within the K 2P channels.potassium channels | single-molecule fluorescence | leak current | combinatorial diversity | heteromerization

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confidence: 99%

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Levitz

Royal

Comoglio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…In rat atria, the mechanosenstive K ϩ currents decline to a plateau of 20-30% of peak within Ϸ1 s (4). These channels share the functional properties of the TREK͞TRAAK K 2P channels and show a similar pattern of expression (13)(14)(15)(16). The K 2P subunits have four transmembrane segments and two P domains in tandem so the functional K 2P channel is a dimer (for reviews, see refs.…”

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confidence: 99%

Desensitization of mechano-gated K _2P channels

Honoré

Patel

Chemin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

126

115

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The neuronal mechano-gated K2P channels TREK-1 and TRAAK show pronounced desensitization within 100 ms of membrane stretch. Desensitization persists in the presence of cytoskeleton disrupting agents, upon patch excision, and when channels are expressed in membrane blebs. Mechanosensitive currents evoked with a variety of complex stimulus protocols were globally fit to a four-state cyclic kinetic model in detailed balance, without the need to introduce adaptation of the stimulus. However, we show that patch stress can be a complex function of time and stimulation history. The kinetic model couples desensitization to activation, so that gentle conditioning stimuli do not cause desensitization. Prestressing the channels with pressure, amphipaths, intracellular acidosis, or the E306A mutation reduces the peak-to-steady-state ratio by changing the preexponential terms of the rate constants, increasing the steady-state current amplitude. The mechanical responsivity can be accounted for by a change of in-plane area of Ϸ2 nm 2 between the closed and open conformations. Desensitization and its regulation by chemical messengers is predicted to condition the physiological role of K2P channels.M ost receptors, including ligand-gated ion channels, desensitize with continuous stimulation. Desensitization is a reversible, use-dependent, form of signal plasticity critical for maintaining the dynamic sensitivity over a wide dynamic range. Desensitization also protects cells from inappropriate persistent activation. Many mechano-gated ion channels desensitize (1-5). There are two basic mechanisms that account for desensitization: adaptation and inactivation. Adaptation refers to the uncoupling of the stimulus from the channel, whereas inactivation refers to a block of the permeation path. In hair cells of the inner ear, deflection opens a mechano-gated channel at the tip of the stereocilium leading to depolarization (6). A fast adaptation mechanism (0.3-5 ms) is attributed to the binding of calcium near the channel after permeation through the open ionic pore (6), i.e., Ca 2ϩ block. A slower adaptation (10-100 ms) occurs when the calcium-dependent molecular motor myosin-1c, which pulls on the channels, slips down the actin cytoskeleton reducing the force applied to the channel (6).Rapid desensitization also occurs in mechanosensitive channels expressed in nonspecialized cells. For instance, the stretchactivated cation channel of Xenopus oocyte opens transiently in response to a step change in patch pressure (5). The decrease in current has been attributed to relaxation of the mechanical stimulus, although as shown in this work, that interpretation may not be a good discriminator. Desensitization of the oocyte channel is fragile and may disappear when patches are repetitively stimulated (5). This fragility was attributed to decoupling of the bilayer from the cytoskeleton (5).Stretch-activated K ϩ channels are present in neurons of both the central and the peripheral nervous systems (7-9), and they also have been described in nonne...

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“…Each subunit of a K 2P channel possesses four TM segments and two P domains, and therefore two subunits are thought to assemble to form a functional dimeric K ϩ channel (4,5). K 2P channels can be divided into six subfamilies based on amino acid homology: TWIK-1 and TWIK-2 (6 -9); THIK-1 and THIK-2 (10); TASK-1, TASK-3, and TASK-5 (11-13); TALK-1, TASK-2, and TALK-2 (14 -16); TREK-1, TREK-2, and TRAAK (17)(18)(19)(20); and TRESK-1 (21). Many of these K 2P channel are able to form functional K ϩ channels when expressed in oocytes or mammalian cells.…”

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Functional Expression of TRESK-2, a New Member of the Tandem-pore K+ Channel Family

Kang¹,

Mariash

Kim

2004

Journal of Biological Chemistry

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A new member of the tandem-pore K ؉ (K 2P ) channel family has been isolated from mouse testis complementary DNA. The new K 2P channel was named TRESK-2, as its amino acid sequence shares 65% identity with that of TRESK-1. Mouse TRESK-2 is a 394-amino acid protein and possesses four putative transmembrane segments and two pore-forming domains. TRESK-2 has a long cytoplasmic domain joining the second and third transmembrane segments and a short carboxyl terminus. In the rat, TRESK-2 mRNA transcripts were expressed abundantly in the thymus and spleen and at low levels in many other tissues, including heart, small intestine, skeletal muscle, uterus, testis, and placenta, as judged by Northern blot analysis. TRESK-2 mRNA was also expressed in mouse and human tissues. In COS-7 cells transfected with TRESK-2 DNA, a time-independent and noninactivating K ؉ -selective current was recorded. TRESK-2 was insensitive to 1 mM tetraethylammonium, 100 nM apamin, 1 mM 4-aminopyridine, and 10 M glybenclamide. TRESK-2 was inhibited by 10 M quinidine, 20 M arachidonate and acid (pH 6.3) at 49, 43, and 23%, respectively. Single channel openings of TRESK-2 showed marked open channel noise. In symmetrical 150 mM KCl, the current-voltage relationship of TRESK-2 was slightly inwardly rectifying, with the single channel conductance 13 picosiemens (pS) at ؉60 mV and 16 pS at ؊60 mV. In inside-out patches, TRESK-2 was unaffected by the intracellular application of 10 M guanosine 5 -O-(thiotriphosphate). These results show that TRESK-2 is a functional member of the K 2P channel family and contributes to the background K ؉ conductance in many types of cells.Mammalian potassium channels are divided into three structural classes based on the number of predicted transmembrane (TM) 1 segments (two, four, or six) and pore-forming (P) domains (one or two). Searching the DNA data base for sequences homologous to previously cloned K ϩ channels led to identification of the class now referred to as tandem-pore or two-pore domain K ϩ (K 2P ) channels (1-4). Each subunit of a K 2P channel possesses four TM segments and two P domains, and therefore two subunits are thought to assemble to form a functional dimeric K ϩ channel (4, 5). K 2P channels can be divided into six subfamilies based on amino acid homology: TWIK-1 and TWIK-2 (6 -9); THIK-1 and THIK-2 (10); TASK-1, TASK-3, and TASK-5 (11-13); TALK-1, TASK-2, and TALK-2 (14 -16); TREK-1, TREK-2, and TRAAK (17-20); and TRESK-1 (21). Many of these K 2P channel are able to form functional K ϩ channels when expressed in oocytes or mammalian cells. Those K 2P channels that form functional K ϩ channels exhibit interesting electrophysiological and pharmacological properties. For example, TASK-1 and TASK-3 are active at rest, highly sensitive to extracellular pH and oxygen concentration (22), and activated by volatile anesthetics (23, 24). TREK-1 and TREK-2 are activated by free fatty acids, protons, increased membrane tension, heat, and volatile anesthetics (25, 26). These channels are functionally expressed...

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TREK-2, a New Member of the Mechanosensitive Tandem-pore K+ Channel Family

Cited by 254 publications

References 38 publications

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Desensitization of mechano-gated K _2P channels

Functional Expression of TRESK-2, a New Member of the Tandem-pore K+ Channel Family

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TREK-2, a New Member of the Mechanosensitive Tandem-pore K+ Channel Family

Cited by 254 publications

References 38 publications

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Heterodimerization within the TREK channel subfamily produces a diverse family of highly regulated potassium channels

Desensitization of mechano-gated K 2P channels

Functional Expression of TRESK-2, a New Member of the Tandem-pore K+ Channel Family

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Desensitization of mechano-gated K _2P channels