Recent advance and possible future in TREK-2: A two-pore potassium channel may involved in the process of NPP, brain ischemia and memory impairment
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Medical Hypotheses (2008) 70, 618–624
http://intl.elsevierhealth.com/journals/mehy
Recent advance and possible future in TREK-2:
A two-pore potassium channel may involved in the
process of NPP, brain ischemia and memory
impairment
Dongyue Huang *, Buwei Yu
Department of Anesthesiology, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine,
Shanghai 200025, PR China
Received 29 May 2007; accepted 6 June 2007
Summary TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family, share 65% amino acid
sequence identity and some similar basic electrophysiological and pharmacological properties with TREK-1. It also has
some specific regulatory pathway and tissue distribution contrasted with TREK-1 and TRAAK. TREK-2 distributes
extensively in CNS and periphery tissue. It can be regulated by G-protein-coupled receptor (GPCR) and may involve in
several of physiological and pathophysiological conditions. The long-chain unsaturated free fatty acids such as
arachidonic acid (AA), PHi, pressure and temperature can increase the activity of TREK-2. The purpose of this review is
to present the recent study and possible importance of TREK-2 in neuropathic pain, thereby emphasizing TREK-2 as one
of the important mechanisms underlying. This information should be very useful and prospective for effective chronic
pain therapy and future analgesic drug development. This review also further predicts the role of TREK-2 in brain
ischemia, memory and other tissue. The specific location and function of TREK-2 in these tissues need further study.
c 2007 Elsevier Ltd. All rights reserved.
Background [1]. The two-potassium channels (K2P) is a collec-
tion of ion channels whose importance in physio-
To date, more than 70 K+ channel genes have been logic mechanisms is still emerging [2,3]. They
identified in mammals and are divided into four appear to be an ancient class of channels; K2P
subfamilies on the basis of their sequence similari- channels are found widely, from single-cell yeast
ties and channel properties. Four families of to plants to higher mammals [4–6]. More than 50
potassium channels are distinguished in neurons: genes with the predicted K2P channel structure
voltage-gated (Kv), calcium-activated (Kca), in- have been identified in Caenorhabditis elegans,
ward rectifier (Kir) and two-pore (K2P) K+ channels as well as 15 human genes [7,8], Fig. 1 shows a den-
drogram depicting the evolutionary relationships
* Corresponding author. Tel.: +86 21 28654139. within the human K2P channel family. The salient
E-mail address: huangdyliang@sjtu.edu.cn (D. Huang). feature of K2P membrane topology is that K2P
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.mehy.2007.06.016Recent advance and possible future in TREK-2 619
studied was the family of TREK, including TREK-1,
TREK-2 and TRAAK. The recent research showed
that TREK-2 is involved in amount of pathologic
process such as acute cerebral ischemia [41].
TREK-2 is greatly possible to associate with noci-
ception according to its electrophysiological prop-
erties and tissue distribution. The purpose of this
review is to present the recent study and possible
importance of TREK-2 in neuropathic pain, thereby
emphasizing TREK-2 as one of the important mech-
anisms underlying neuropathic pain. This informa-
tion should be very useful and prospective for
effective chronic pain therapy and future analgesic
drug development. This review also further pre-
dicts the role of TREK-2 in brain ischemia, memory
Figure 1 The human two-pore-domain K+ (K2P) chan-
and other tissue.
nels. A phylogenetic tree of the K2P channel family is
shown, with the different nomenclatures indicated.
Human K2P channels are classified into six structural
and functional subgroups. The TREK subgroup (indicated The molecular structure and tissue
in green) comprises TREK-1 (KCNK2), TREK-2 (KCNK10) distribution of TREK-2
and TRAAK (KCNK4), which share structural and many
functional properties, including activation by membrane TREK-2, as a new member of the mechanosensitive
stretch and lipids such as arachidonic acid and lysophos- tandem-pore K+ channel family, is firstly reported
phatidylcholine. The TASK subgroup (indicated in pink) by Bang and Lesage. It is a 538-amino acid protein
comprises channels that are inhibited by extracellular
and share 65% amino acid sequence identity with
acidosis, whereas the TALK channels (indicated in blue)
TREK-1, has a short N terminus, an extended extra-
are activated at alkaline extracellular pH. TREK-1, TREK-
2, TASK-1, TASK-2 and TASK-3 are activated (indicated in cellular loop between M1 and P1, and a long C ter-
green on the tree), whereas THIK-1, TWIK-2, TALK-1, and minus, structural features typical of nearly all 4TM
TALK-2 are inhibited (indicated in red on the tree), by K+ channels (Fig. 2) [12]. Genomic organization of
volatile general anaesthetics. Several human K2P chan- TREK-2 is very close to the genomic organization
nels have little or no functional expression (indicated in of both TRAAK and TREK-1 channel genomic organi-
light grey on the tree). TRAAK is not modulated by zations [13]. The literature reported that TREK-1
volatile general anaesthetics and the sensitivity of TRESK and TRAAK mRNA expression was predominantly
has not yet been reported (indicated in dark grey). Cited CNS specific in contrast to the closely related
from Nicholas et al. [46] (For interpretation of the TREK-2, which was expressed in both CNS and
references in color in this figure legend the reader is
peripheral tissues [14]. However, subsequent stud-
referred to the web version of this article).
ies showed that there are even more widespread
distribution of TREK-1 and TRAAK than that of
TREK-2 in peripheral tissue such as in the rat heart,
channels have four transmembrane domains (TM1- mesenteric and pulmonary arteries, human myo-
4), two pore-forming domains (P1.P2) [4,9,10], metrium [15–17]. The K2P distribution analysis in
while other K+ channels are characterized by hav- CNS proved that the TREK-2 probe detected two
ing two, six or eight transmembrane segments transcripts of 4 and 7.5 kb, and expression of
and share one conserved pore-forming domains TREK-2 was primarily restricted to the cerebellar
[11]. The K2P channels can produce leak current granule cell layer and TREK-1 was highest in the
that contribute to set and stabilize the resting po- striatum and in parts of the cortex (layer IV) and
tential and thus influences the cell excitability in hippocampus (CA2 pyramidal neurons) [18]. It is re-
physiological condition, independent of the time ported that TREK-2 channels play a relative low
and voltage, which is distinguished from other K+ role in composed of the standing outward K+ (IKso)
channels. The K2P channels are insensitive to clas- in cerebellar granula neurons that modulates the
sic K+ channel blocker such as tetraethylammo- resting membrane and cell excitability [19].
nium, apamin, 4-aminopyridine and glybenclamide. TREK-2 is also found in the magnocellular neurose-
In the 2P/4TM K+ channels family, there are six cretory cells (MNCs), cultured rat brain astrocytes
subfamilies according to the difference of channel and insulin-secreting MIN6 cells [20–22]. Future
structure and regulation: TWIK, THIK, TASK, TALK, in situ hybridization and immunohistochemical
TREK, TRESK. In this K2P channel, the most deeply localization studies is needed to identify in which620 Huang and Yu
of protein kinase A and C on TREK-2 is that phos-
phorylation by protein kinase A caused a signifi-
cant reduction of TREK-2 current, whereas
phosphorylation by protein kinase C had no effect
[12]. TREK-2 like TREK-1 and TRAAK, is a mecha-
nosensitive K+ channel, and increased channel
activity rapidly when applied negative pressure
(0 to 80 mmHg) [23]. TREK-2 is activated by
long-chain unsaturated free fatty acids such as
arachidonic acid (AA), linoleic acid and oleic acid
and insensitive to saturated free fatty acids such
as stearic acid and palmitic acid even up to high
concentration [12,23].
TREK-2 is reversibly activated by intracellular
LPA at atmospheric pressure, and thus channel
mechano-sensitivity is drastically and reversibly al-
tered. A possible mechanism may involve in a mem-
brane effect of LPA [24,25]. Zn2+ can enhance the
TREK-2 current in a dose-dependent manner [26].
Otherwise, fenamates can markedly stimulate the
TREK-1, TREK-2 and TRAAK and diltiazem (1 mM)
inhibited TREK-1 and TREK-2, but not TRAAK. So
diltiazem may be a specific blocker for TREK-2.
These novel findings could help to further under-
stand channel functions of the mechano-gated 2P
Figure 2 TREK-2 sequences and predicted membrane domain K+ channels [27]. TREK-2 is temperature-
topology. (A) Nucleotide and amino acid sequences of rat sensitivity and the thresholds for activation were
TREK-2. Four transmembrane segments and two pore- approximately 25 °C. In cerebellar granule and dor-
forming domains are underlined. Consensus sites for N- sal root ganglion neurones, TREK-1, TREK-2 and
glycosylation (boxed) and phosphorylation by protein TRAAK were generally inactive in the cell-attached
kinase A (m) and protein kinase C (d) are shown. These
state at 24 °C, but became very active at 37 °C.
sites were identified using the MacVector program. (B)
Hydropathy plot of TREK-2 amino acid sequence analyzed
These results show that TREK-2 in temperature-
using the Kyte-Doolittle algorithm shows four potential sensitive channels, is active at physiological body
transmembrane segments and two potential pore-form- temperature, and therefore would contribute to
ing regions. (C) Deduced topology of TREK-2. N-Gly, N- the background K+ conductance and regulate cell
glycosylation; PKA and PKC, protein kinase A and C, excitability in response to various physical and
respectively. Cited from Bang et al. [12]. chemical stimuli [28]. Application of H2O2 in CHO
cells specifically increased TREK-2 currents re-
corded using a nystatin perforated whole cell tech-
cells and at what levels TREK-2 is expressed in the nique and that MLCK activation is involved in this
CNS and peripheral tissues. process [29].
Electrophysiological and pharmacologi- Predicted physiological role of TREK-2
cal properties of TREK-2
TREK-2 and neuropathic pain
Previous studies have shown that TREK-2 passes
an instantaneous and non-inactivating current in The TREK-2 is inhibited by PKA phosphorylation be-
the nA range and is an inwardly rectifying K+ cause increasing the intracellular cAMP level led to
channel in symmetrical 150 mM K+ [23]. TREK-2 inhibition of TREK-2 activity at 0 mV [Fig. 3].The
is insensitive to classic potassium blocker such level of TREK-2 activity can be regulated by three
as tetraethylammonium, quinidine when applied different types of G-protein-coupled receptors.
extracellularly, stimulated markedly by acidic pH The application of Gs-, Gq-coupled receptor, is
and inhibited mildly by alkaline pH. TREK-2 pos- associated with a decrease of TREK-2 activity,
sesses potential phosphorylation sites for both which is associated with activation of phospholi-
protein kinase A and C. The effects of activators pase C. Conversely, activation of the Gi-coupledRecent advance and possible future in TREK-2 621
Figure 3 Activation of TREK-2 by polyunsaturated fatty
acids and lysophosphatidylcholine and inhibition by
cAMP. (A) Activation by arachidonic acid (AA) of the
whole-cell TREK2 current. The I–V curves were obtained
with a voltage-ramp protocol of 800 ms-duration starting
from a holding potential of 80 mV. (B) Activation by
lysophosphatidylcholine (LPC). The protocol was as in A.
(C) Effect of fatty acids on TREK2. DHA, docosahexaenoic
acid; LA, linoleic acid; PA, palmitic acid. (D) Regulation
of TREK2 channel activity by cAMP. Inhibition of the
current after external application of 500 lM chlorophe- Figure 4 Regulation of TREK-2 by G-protein-coupled
nylthio-cAMP (CPT-cAMP). The voltage protocol was as in receptors. Left, evolution of the whole-cell TREK-2
A. current under control conditions (1) at the steady-state
effect after receptor activation (2) and after wash (3).
The voltage-clamp protocol consists of a voltage-ramp of
leads to a stimulation of TREK-2 activity [Fig. 4] 800 ms-duration starting from a holding potential of
80 mV applied every 10 s. The current was monitored at
[13]. Activator of Gq-coupled M3 muscarinic recep-
+100 mV. Right, corresponding I–V curves of the exper-
tor, acetylcholine (ACh), induces the inhibition of iments shown on the left. The TREK-2 channel was co-
TREK-2 and occurs primarily via PKC-mediated expressed together with 5HT4sR (A), mGluR2 (B), or
phosphorylation [30]. TREK-2 regulated by GPCR mGluR1 (C) receptors. The receptors were activated by
pathways will probably indicate that TREK-2 activ- application of 5-hydroxytryptamine (5HT) for 5HT4sR and
ity in neurons is probably fine-tuned by a variety of glutamate for mGluR1 and 2. No effect on TREK2 current
neurotransmitters. TREK-2 will probably turn out to were seen after 5-hydroxytryptamine and glutamate
be an important channel in charge of tuning neuro- applications on COS cells transfected with only TREK-2.
nal excitability in response to a variety of neuro- The Figs. 3 and 4 is cited from Lesage et al. [13].
transmitters and hormones and is therefore a
natural target of mediators of pain that exert their
action via these pathways. Also, TREK-1, which is in vivo [33]. After the neuron is injured or con-
most homology with TREK-2, involved in polymodal stricted, important changes occur in DRG axotom-
pain perception, is highly expressed in small sen- ized neurons so that some of quiescent neurons
sory neurons and extensively colocalized with begin to show ongoing discharges that last many
TRPV1, the capsaicin-activated nonselective ion days or weeks. This ectopic discharge has great
channel [31]. Recent studies have shown that relation with the hyperexcitability of DRG neurons
mRNA transcripts of four major types of K+ chan- after axotomy. Then, ectopic discharge go into the
nels are identified in dorsal root ganglion [13]; spinal posterior horn and even transmit to higher
these four K+ channels are TRESK, TREK-1, REK-2, central nerve system, which lead to central sensiti-
and TRAAK. TREK-2 provide the major background zation to pain. Intense noxious stimuli to nerve and
K+ conductance in cell body of small (diameter tissue can trigger increased excitability of nocicep-
10–16)- to medium (diameter 17–25)-sized DRG tive neurons in the spinal cord and cause the re-
neurons at 37 °C [13,32], is expected to play an ac- lease of unsaturated free fatty acid, the change
tive role in the modulation of excitability of DRG of PH and temperature, and edema leading to the
neurons and particularly in the regulation of the negative mechanical stretch in local position,
resting membrane potential if it is active at rest which can activate the TREK-2 channel [34–36].622 Huang and Yu
Evidence gathered from the electrophysiological established. ERK integrate the signal of PKA and
properties of TREK-2 and pathological change of PKC in the superficial of spinal cord and play a sub-
neuropathic pain suggest that TREK-2 be activated stantial role in enhancing the excitability of DRG
in the process of neuropathic pain by decreasing neuron after CCI [39,40]. However, further details
the neuronal excitability especially the DRG neu- about whether ERK is involved in the cell signal
rons. It is a paradox contrast with the common idea pathway of TREK-2 as a downstream of the PKA
to the role of potassium channel in NPP. Previous and PKC need to be examined in future studies.
literature suggests that potassium channels play The inhibition of PKA or/and PKC, ERK may relieve
an important role in influencing ectopic discharge the neuropathic pain through regulatory current of
of DRG neurons. The hyperexcitability of DRG neu- TREK-2. Others, it would be prospective to inter-
rons in chronic pain modal always accompany with fere with the process of NPP by selectively manip-
reduction of potassium currents. So the exact ulating the TREK-2 gene.
change of TREK-2 might be upregulated or down- On the other hand, numerous studies demon-
regulated. It is not sure that the TREK-2 change strate that the opening of several potassium chan-
plays a blocked or promoted role in the process nels participate in the antinociception induced by
of neuropathic pain. To confirm the speculation, some drugs such as opioid analgesic, nonsteroidal
the reverse transcription polymerase chain reac- anti-inflammatory drugs (NSAIDs), tricyclic antide-
tion (RT-PCR) and western blot analysis are needed pressants, etc [1]. The possible involvement of
to analyze the mRNA and protein expression of TREK-2 opening in the antinociception induced by
TREK-2 in some neuropathic pain model such as these drugs remains unexplored to date. Research
CCI model by Bennett and Xie [37]. The immunohis- about that would help better understanding the
tochemistry and situ hybridization are performed mechanism of these drugs and why or why not
to observe the number of positive neurons and these drugs are effective to the NPP.
the level of phosphorylation of TREK-2. Also, the
TREK-2 channel character in DRG neurons of neuro- TREK-2 and neuroprotection
pathic pain model must be studied by whole-cell
recording or single-channel recording including In rat ischemia model, TREK-1, TREK-2, and TRAAK
the current–voltage curve (I–V curve), unitary showed enhanced expressions both in cortex and
conductance, and the ion channel kinetics com- hippocampus at mRNA and protein level after the
pared to the normal DRG neurons. Of course, the middle cerebral artery occlusion (MCAO) and even
higher central neuron system needs to be re- higher expression levels of TREK channels 24 h
searched such as spinal cord, hippocampus and after MCAO surgery in the survival neurons. It is
cerebral cortex. It is prospective to analyze the predicted that TREK channels be activated by the
function of TREK-2 in DRG neurons using the CCI pathological changes in the microenvironment,
model of TREK-2-/- mice and various techniques but in a relatively long period, their genes are acti-
mentioned above. At present, pharmacological vated and more functional proteins are expressed.
tool such as the selective agonist for TREK-2 is Thus the TREK channels probably provide a protec-
not yet available and genes of TREKs are highly tive function during brain ischemia by the increase
homologous, making it difficult to test this hypoth- of the channels activation, which can cause the ef-
esis in future experiments. Anyway, the increase of flux of K+ from cells, membrane hyperpolarization
this inwardly rectifying potassium current contrib- and decrease the cell excitability [41]. But in
utes to the alleviation of abnormal pain sensation chronic cerebral ischemia model, the gene expres-
in neuropathic pain such as hyperalgia and allo- sions of TREK-1 and TRAAK were increased mark-
dynia. It is possible that the specific activator of edly at 3 days (97% and 87%, respectively) and 30
TREK-2 becomes an effective drug on chronic pain days (63% and 47%, respectively) in hippocampus
if the above speculation is sure. To do this, the after permanent bilateral carotid artery ligation
activator of TREK-2 can be applied to the injury (BCAL). However, TREK-2 gene expression level
site or directly to the DRG [38], then the ectopic had no change [42]. Therefore, the protective
discharge and behavioral signs of mechanical and function of TREK-1, REEK-2 and TRAAK is different
heat allodynia are evaluated. in different ischemia state. TREK-2 can be stimu-
lated by application of the inhalational anesthetic
The possible signal transduction pathway chloroform, halothane, and isoflurane at a clinical
and role in some drugs dose [13]. At present, solid experimental evidence
supports neuroprotection by anesthetic agents that
To elucidate the details of role of TREK-2, delinea- the mechanisms appear to involve in suppression of
tion of the precise signal pathway needs to be excitatory neurotransmission, and potentiation ofRecent advance and possible future in TREK-2 623
inhibitory activity, which may contribute to the References
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