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The Journal of Neuroscience, February 1, 1998, 18(3):868-877
An Open Rectifier Potassium Channel with Two Pore Domains in
Tandem Cloned from Rat Cerebellum
Dmitri
Leonoudakis1,
Andrew T.
Gray1,
Bruce D.
Winegar1,
Christoph H.
Kindler1,
Masato
Harada1,
Donald M.
Taylor1,
Raymond A.
Chavez2,
John R.
Forsayeth2, and
C. Spencer
Yost1
1 Department of Anesthesia, University of California
San Francisco, San Francisco, California 94143-0542, and
2 Neurex Corporation, Menlo Park, California 94025
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ABSTRACT |
Tandem pore domain K+ channels represent a new
family of ion channels involved in the control of background membrane
conductances. We report the structural and functional properties of a
TWIK-related acid-sensitive K+ channel (rTASK), a
new member of this family cloned from rat cerebellum. The salient
features of the primary amino acid sequence include four putative
transmembrane domains and, unlike other cloned tandem pore domain
channels, a PDZ (postsynaptic density protein, disk-large, zo-1)
binding sequence at the C terminal. rTASK has distant overall homology
to a putative Caenorhabditis elegans
K+ channel and to the mammalian clones TREK-1 and
TWIK-1. rTASK expression is most abundant in rat heart, lung, and
brain. When exogenously expressed in Xenopus oocytes,
rTASK currents activate instantaneously, are noninactivating, and are
not gated by voltage. Because rTASK currents satisfy the
Goldman-Hodgkin-Katz current equation for an open channel, rTASK can
be classified an open rectifier. Activation of protein kinase A
produces inhibition of rTASK, whereas activation of protein kinase C
has no effect. rTASK currents were inhibited by extracellular acidity.
rTASK currents also were inhibited by Zn2+
(IC50 = 175 µM), the local anesthetic
bupivacaine (IC50 = 68 µM), and the
anti-convulsant phenytoin (~50% inhibition at 200 µM).
By demonstrating open rectification and open probability independent of
voltage, we have established that rTASK is a baseline potassium
channel.
Key words:
potassium channel; open rectifier; local anesthetics; pH; cloning; cerebellum; Xenopus oocyte; baseline channel
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INTRODUCTION |
Potassium channels are pore-forming
integral membrane proteins that selectively pass K+
across cellular membranes. These channels are involved in a wide variety of cellular processes, including control of the resting membrane potential, K+ homeostasis, neuronal firing,
and signal transduction. K+ channel physiology is
therefore diverse and reflected in well-defined structural and
functional differences (Hille, 1992 ; Christie, 1995). However, all
K+ channels cloned previously contain at least one
signature sequence, the pore (P) or H5 region, that is thought to line
the ion conducting pathway and is critical for determining the
K+ selectivity of conduction (Durell and Guy, 1992;
Jan and Jan, 1992; MacKinnon, 1995).
Recently, a new family of K+ channels has been
identified, with members having two P domains in tandem within their
primary amino acid sequences (Ketchum et al., 1995). The cloned members of this family are not voltage-gated and may contribute to leak currents setting the membrane potential. TOK1, from the budding yeast
Saccharomyces cerevisiae, was the first channel of this type
to be cloned (Ketchum et al., 1995) and, by hydropathy analysis, displays eight transmembrane domains. Other cloned tandem pore domain
K+ channels appear to have four transmembrane
domains and include the weak inward rectifier TWIK-1 (cloned from both
human and mouse) (Lesage et al., 1996b, 1997), the mammalian outward
rectifier TREK-1 (Fink et al., 1996), and the open rectifier ORK1
(cloned from Drosophila) (Goldstein et al., 1996). TWIK-1 is
highly expressed in hippocampus and cerebral cortex and shares 28%
homology with the outward rectifier TREK-1 that is also found in
hippocampus, cerebral cortex, and cerebellum. These channels may be the
first cloned examples of a large family of K+
channels, as evidenced by the recent identification of at least 23 tandem pore domain K+ channel genes from sequences
derived from the Caenorhabditis elegans genome project (Wei
et al., 1996).
Using K+ channel P region homology and BLAST (basic
local alignment search tool), we identified and cloned a cDNA from a
rat cerebellum library that encodes a member of the tandem pore domain K+ channel family. When this member is expressed in
Xenopus oocytes, functional K+ channels
are produced that exhibit open rectification, noninactivation, and
marked sensitivity to extracellular pH and local anesthetics. In
addition, this new member is the first cloned tandem pore domain K+ channel to contain a predicted motif for synaptic
localization by postsynaptic density protein. Because of the structural
homology with recently published full-length human and partial mouse
clones (Duprat et al., 1997), we have named our rat clone rTASK, for TWIK-related acid-sensitive K+ channel.
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MATERIALS AND METHODS |
Northern blots. A 400 base pair (bp) restriction
fragment corresponding to the entire cloned sequence from accession
number W36914 expressed sequence tag (EST) was generated using
EcoRI and NotI. This fragment was randomly primed
(RadPrime DNA labeling system; GIBCO BRL, Grand Island, NY) with
[ -32P]dCTP (Amersham, Arlington Heights, IL) included
in the reaction mixture to produce a labeled probe for hybridization
against commercially available human brain and rat multiple tissue
Northern blots (Clontech, Palo Alto, CA) and an additional blot of rat
cerebellar RNA alone. A labeled control probe was made in the same way
by randomly priming the sequence for  -actin. The blots were
hybridized with probe at 65°C overnight in ExpressHyb hybridization
solution (Clontech), washed three times with 2× SSC and 0.05% SDS at
room temperature, and washed twice with 0.1× SSC and 0.1% SDS at
55°C for 20 min each. Autoradiographs were made by exposing the blots
to x-ray film at  80°C.
Library construction and screening. mRNA was isolated
directly from adult rat cerebellum (Fast Track 2.0; Invitrogen, San Diego, CA) and used to construct an oligo-dT-primed cDNA library cloned
into the UniZAP XR phage vector (Stratagene, La Jolla, CA). One million
phage clones were screened. Plaques were transferred to charged nylon
membranes (MSI, Westboro, MA) and hybridized at 65°C overnight with
the -32P-labeled EcoRI-NotI 400 bp
EST fragment in ExpressHyb hybridization solution. Membranes were
washed three times with 2× SSC and 0.05% SDS at room temperature,
washed twice with 0.1× SSC and 0.1% SDS at 55°C for 20 min each,
and exposed to x-ray film for 72 hr at 80°C. Positive clones were
isolated and excised from the UniZAP XR phage vector into pBluescriptSK
(Stratagene).
Sequence analysis. The largest positive clone (2.1 kb
insert) was sequenced on both strands using a dye terminator kit with an automated sequencer (Applied Biosystems, Foster City, CA). Analyses
of DNA and predicted protein sequences were performed using Lasergene
(DNASTAR, Madison, WI). Protein motifs were identified using the ExPASy
server (University of Geneva, Switzerland) to search the Prosite
database.
Transcript preparation. The plasmids containing the rTASK
open reading frame, ORK1 (Goldstein et al., 1996), and TOK1 (Ketchum et
al., 1995) were linearized by restriction digestion, purified with
phenol and chloroform, and used as template. Capped transcript was
prepared using the T3 and T7 mMessage mMachines (Ambion, Austin, TX).
cRNA was precipitated with lithium chloride and resuspended in oocyte
saline (OS; composition in mM, 100 KCl and 20 NaCl in diethylpyrocarbonate-treated water) to a final concentration of ~0.5
mg/ml.
Oocyte removal and injection. These studies were approved by
the University of California San Francisco Committee on Animal Research. Methods used for oocyte preparation were similar to those
described previously (Quick and Lester, 1994). Adult female Xenopus laevis were anesthetized in 0.3% 3-aminobenzoic
acid ethylester on ice for 30 min. After removal, oocytes were
incubated with gentle agitation in oocyte Ringer's solution with
Mg2+ (OR-Mg; composition in mM, 82 NaCl,
2 KCl, 5 HEPES, and 20 MgCl2, pH 7.4) with 2 mg/ml
collagenase A (Boehringer Mannheim, Indianapolis, IN) at room
temperature, washed twice with enzyme-free OR-Mg, washed twice with
modified Barth's solution with HEPES [composition in mM,
88 NaCl, 1 KCl, 10 HEPES, 7 NaHCO3, 1 CaCl2, and 1 Ca(NO3)2, pH 7.0], and then
selected (stage V and VI only) for injection. On the same day as
isolation, oocytes were injected with 5-10 ng of either rTASK, ORK1,
or TOK1 cRNA or with OS as control. After injection, oocytes were
maintained in modified Barth's solution with HEPES with 50 mg/ml
gentamycin, 2.5 mM sodium pyruvate, 5% heat-inactivated
horse serum, and 5 mM theophylline at 18°C with gentle
rotation.
Two-electrode voltage-clamp recordings. All
electrophysiology experiments were performed at room temperature
(21-23°C) 1-3 d after injection. rTASK, ORK1, and TOK1 currents
were measured by two-electrode voltage clamp (Axoclamp 2A; Axon
Instruments, Foster City, CA). Microelectrodes were backfilled with 3 M KCl and had resistances of 0.3-1.5 M . Pulse protocols
were applied from a holding potential of 80 mV using 1 sec voltage
pulse steps ranging from 140 to +40 mV in 20 mV increments, with 1.5 sec interpulse intervals. Except where noted, all two-electrode
voltage-clamp experiments were performed using frog Ringer's solution
(composition in mM, 115 NaCl, 2.5 KCl, 1.8 CaCl2, and 10 HEPES, pH 7.6) as perfusate.
Recordings were obtained in a 25 µl recording chamber at flow rates
of 3-5 ml/min. Saline-injected oocytes were used as controls,
undergoing the same treatments as transcript-injected oocytes. To
quantify responses, we averaged leakage currents of saline-injected
oocytes and subtracted these averages from currents of rTASK oocytes.
For most experiments, signals were filtered using an eight pole
low-pass Bessel filter (Frequency Devices, Haverhill, MA) set at a 40 Hz cutoff before sampling at 100 Hz. In some instances, signals were
filtered at 100 Hz before sampling at 1 kHz.
Single-channel recordings. Standard methods were used to
record single-channel activity from cell-attached or excised patches according to the technique described by Hamill et al. (1981). Patch
electrodes were pulled from borosilicate capillary tubes, the shanks
were coated with Sylgard (Dow Corning, Midland, MI), and the tips were
heat-polished. Currents were recorded with a List EPC-7 amplifier and
digitally stored on videotape at a sample rate of 44.1 kHz. The current
records were analyzed on an LSI 11/73 computer (Indec Systems,
Capitola, CA) after filtering with an eight pole Bessel filter (3 dB
at 2 kHz) and sampling at 10 kHz. All experiments were performed at
room temperature (21-23°C). Before recordings were performed, the
oocyte vitelline membrane was removed with a pair of fine forceps after
a 10 min incubation in hypertonic saline (composition in
mM, 200 potassium aspartate, 20 KCl, 1 MgCl2, 10 EGTA, and 10 HEPES, pH 7.4).
rTASK channels were studied primarily in outside-out patches to control
both external and internal solutions and to reduce contamination of
records by endogenous mechanosensitive channels (Methfessel et al.,
1986). For outside-out patches, the patch electrode filling solution
contained (in mM): 150 potassium aspartate, 10 HEPES, 4 glucose, 1 EGTA, and 5 MgCl2, pH 7.4, whereas the bathing solution contained (in mM): 150 NaCl, 3 KCl, 10 HEPES, 14 glucose, 2 CaCl2, and 1 MgCl2, pH 7.4. Before seal formation, the voltage
offset between the patch electrode and the bath solution was adjusted
to produce zero current. The recording micropipette resistances ranged
from 3 to 5 M, and seal resistances ranged from 20 to 40 G. The
unitary current was determined by positioning a cursor in the center of
the open channel noise and measuring the amplitude of the current
between the open channel and closed channel level.
Data analysis. Except where noted, data are reported from at
least three oocytes and from more than one set of injected oocytes. Mean values are expressed ± SEM with n values
indicating the number of oocytes studied. Statistical significance is
defined by p < 0.05. The Woodhull model (Woodhull,
1973) of voltage-dependent inhibition was used to model pH,
Zn2+, and bupivacaine inhibition of rTASK currents.
The Woodhull model parameters were estimated by multiple regression
(JMP, SAS Institute, Cary, NC).
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RESULTS |
Candidate clone identification
Pore and adjacent regions of all identified tandem pore domain
K+ channels were aligned using the MegAlign program
(Clustal algorithm; Lasergene; DNASTAR). Consensus protein sequences of
each P domain from these alignments were used to perform BLAST searches
of the EST database (Altschul et al., 1990). These searches identified a clone (accession number W36914) from a mouse cDNA library (19.5 days
after conception) that contained a novel P region. This clone was
referred to as "EST400" because it contained a 400 bp insert of
cDNA. Secondary searches of the EST database revealed three other
clones (accession numbers W01960, W99136, and W36852) that formed a
contiguous sequence of 901 bp. When translated, this contiguous
sequence of four ESTs contained an open reading frame (ORF) with two P
regions in tandem. EST400 was then used to probe an adult rat
cerebellum cDNA library to identify a full-length sequence. Six
positive clones were identified and excised as plasmids with the
largest containing a 2.1 kilobase pair (kb) cDNA insert.
Sequence analysis
The 2.1 kb insert of this clone was completely sequenced on both
strands and found to contain an ORF of 1233 bp encoding a 411 amino
acid polypeptide with a calculated molecular weight of 45.3 kDa that we
have termed rTASK (Fig.
1A). Strong translation initiation sequences were found adjacent to the start codon (Kozak, 1996). A hydrophobicity plot (Kyte-Doolittle method) indicates four
potential transmembrane domains, here designated M1-M4 (Fig. 1B). The predicted protein sequence contains two P
domains, P1 located between M1 and M2 and P2 located between M3 and M4.
rTASK does not have an N-terminal signal sequence, suggesting that the N terminal is intracellular (Walter and Lingappa, 1986). rTASK also
contains potential phosphorylation sites for tyrosine kinase, protein
kinase C (PKC), and protein kinase A (PKA). In addition, a PDZ
[postsynaptic density protein (PSD), disk-large, zo-1] interaction domain (Kornau et al., 1995; Cohen et al., 1996) occurs at the extreme
C terminal (SSV) and overlaps the putative PKA phosphorylation sites.
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Figure 1.
Sequence analysis of rTASK. A,
Nucleotide and deduced amino acid sequence of rTASK. The four putative
transmembrane domains (M1-M4) are enclosed in
boxes. Underlined segments indicate pore regions (P1, P2). Sites for N-linked
glycosylation (asterisk) and phosphorylation by tyrosine
kinase (filled circle), protein kinase C
(filled squares), and protein kinase A
(filled triangles) are indicated. The
circled amino acids at the C terminal indicate the
postsynaptic density (PSD) binding motif. B, Hydropathy
plot showing transmembrane domains (M1-M4) and
the P regions (P1, P2) using the
Kyte-Doolittle algorithm. C, Predicted transmembrane topology of rTASK with labeled transmembrane domains and pore regions.
The GenBank accession number of the rTASK clone is AF031384.
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Figure 1C shows the predicted topology based on these data.
Sequence alignment revealed weak homology with two other pore domain
K+ channels overall (37.1% similarity with the
C. elegans predicted protein C40C9.1; 19.5% with TREK-1).
However, higher level homology appears when the alignments are
restricted to the P1 and P2 regions (69.0 and 58.6% similarity for
C40C9.1; 61.9 and 58.6% for TREK-1; Fig.
2). Residues farther downstream from P1
also show significant conservation with other tandem pore domain
clones.
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Figure 2.
Sequence comparison of related tandem pore
domains. Protein sequence alignments (dark areas) of the
P1, post-P1, P2, and post-P2 regions of rTASK with the homologous
regions of the three most closely related C. elegans
tandem pore domain K+ channels and of TREK-1,
TWIK-1, ORK1, and TOK1 are shown.
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Tissue distribution
Northern blot analysis of rat mRNA (Fig.
3) showed transcripts of ~4 kb in heart
 lung > brain liver, kidney, and skeletal muscle. A
transcript corresponding to our cloned sequence could also be detected
in rat cerebellum. A human multiple tissue Northern blot, when screened
with an rTASK probe, showed abundant expression of three
different-sized bands (2.7, 4.4, and 7 kb) in placenta, lung, and
pancreas, with only the smaller 2.7 and 4.4 kb transcripts in heart,
brain, and kidney at relatively lower abundance (data not shown).
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Figure 3.
Northern blot analysis of rTASK distribution in
adult rat tissue. A rat multiple tissue Northern blot was probed at
high stringency with a probe made from the EST400 sequence. The blot
was reprobed with a -actin cDNA probe for a control. Added
lane shows the presence of rTASK transcript in rat
cerebellum.
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Functional expression of rTASK channels
cRNA was transcribed from the plasmid containing rTASK and
injected into Xenopus laevis oocytes. Oocytes injected with
transcript exhibited large (0.5-8 µA) outward noninactivating
currents under two-electrode voltage clamp. These currents were not
observed in saline-injected or uninjected oocytes. No evidence of
inactivation of the channel was observed with long voltage pulses
(1-10 sec in duration). Oocytes that expressed rTASK also had more
negative resting membrane potentials (Em) than
did control saline-injected oocytes (for rTASK oocytes,
Em = 66 ± 2 mV; n = 21;
for control saline-injected oocytes, Em = 33 ± 4 mV; n = 10).
To determine the ion selectivity of the channel, we conducted
experiments using varying concentrations of extracellular
K+. The slope of the plot of reversal potential
versus K+ concentration was 54 ± 3 mV per
10-fold change in K+ concentration, close to that
predicted for a potassium-selective channel (Fig.
4A). At high levels of
extracellular potassium (100 mM), large inward currents
were observed at negative holding potentials of rTASK-injected oocytes,
as predicted by the Goldman-Hodgkin-Katz current equation for an open
channel (Fig. 4B).
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Figure 4.
Biophysical properties of rTASK currents in
Xenopus oocytes studied with two-electrode voltage
clamp. A, Reversal potential as a function of
extracellular K+ for rTASK-expressing oocytes.
Reversal potential changed by 54 ± 3 mV per 10-fold change in
extracellular K+, as estimated with linear
regression (regression line shown). B,
Whole-cell current-voltage relation with either 5 mM
(filled circles) or 100 mM
(open circles) extracellular K+. The
current-voltage relations for an open K+-selective
channel estimated from the Goldman-Hodgkin-Katz current equation are
drawn as solid lines.
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Pharmacology of rTASK
The pharmacological properties of rTASK expressed in
Xenopus oocytes are summarized in Table
1 for a set of K+
channel blockers and modulators. We found rTASK was moderately sensitive to inhibition by Zn2+, quinidine,
phenytoin, and mast cell degranulating (MCD) peptide. Zn2+ inhibition was dose-dependent with an
IC50 value of 175 µM. Likewise, external
tetraethylammonium (TEA+) produced a dose-dependent
inhibition over the range from 10 to 100 mM but did not
inhibit more than ~30-40% of rTASK current. Quinidine, which
inhibits TWIK-1 currents by 50% at 95 µM (Lesage et al.,
1996b), inhibited rTASK currents ~30% at 100 µM. The
anti-convulsant phenytoin (200 µM) in 1% DMSO
(dimethylsulfoxide) inhibited rTASK currents by almost 50%. DMSO alone
had a small effect on rTASK currents and on saline-injected oocytes
(inhibition of 16 ± 5%).
Several other compounds known to have modulatory effects on
K+ channels also were examined. Increases in
extracellular Mg2+ (up to 10 mM) caused
minimal inhibition (14%). Barium produced only minimal rTASK
inhibition (19%) at 100 µM. Unlike TREK-1, the
K+ currents of which are inhibited almost completely
by N-methyl-D-glucamine (NMDG) substitution for
Na+ in the external buffer (Fink et al., 1996),
rTASK had only weak sensitivity to NMDG substitution, but this
inhibition was greater than that for ORK1, which is insensitive to NMDG
substitution (Goldstein et al., 1996). rTASK was insensitive or
minimally affected (<15%) by the following K+
channel inhibitors: 4-aminopyridine (10 mM), agitoxin (1 nM), dendrotoxin (100 nM), margatoxin (10 nM), charybdotoxin (200 nM), and glibenclamide
(30 µM). The K+ channel opener
cromakalim (100 µM) also had minimal effect on rTASK
currents.
rTASK currents were reversibly sensitive to changes in extracellular
pH. At extracellular pH 6.4, rTASK currents were suppressed to a level
close to the currents of saline-injected oocytes (Fig. 5A), but further decreases in
extracellular pH did not alter rTASK current. At extracellular pH
values above 7.6, rTASK currents were potentiated (Fig.
5B,C). The metabolic inhibitor
dinitrophenol (DNP), which lowers intracellular pH by uncoupling the
H+ gradient in mitochondria (Snoeij et al., 1986),
inhibited rTASK currents by >50% after 6 min of perfusion (Table 1).
The magnitude of this inhibition was similar to that reported for
TWIK-1 (Lesage et al., 1996b).
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Figure 5.
Extracellular pH sensitivity of rTASK.
A, Representative current responses from rTASK
cRNA-injected oocytes at pH 7.6 and 6.4 (voltage pulses from 120 to
+40 mV). B, Current-voltage curves of rTASK-injected
oocytes at several different extracellular pH values. Currents from
control saline-injected oocytes were unchanged over this pH range.
C, Effect of extracellular pH on rTASK currents (80 to
+40 mV pulse). Data have been normalized to currents measured at pH
7.6. Mean values are shown with the SE.
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The effects of several anesthetic agents on rTASK were investigated.
The local anesthetic bupivacaine showed dose-dependent inhibition of
rTASK with an IC50 of 68 µM (Fig.
6). Lidocaine also inhibited rTASK, but
not as potently as bupivacaine. Interestingly, the positively charged
lidocaine analog QX314 had no effect on rTASK currents (Table 1).
Ethanol caused dose-dependent inhibition of rTASK with minimal
inhibition at a clinical concentration (17 mM, 9%
inhibition) and moderate inhibition at a higher concentration (170 mM, 41% inhibition). Neither the volatile general
anesthetic isoflurane (0.015-0.03 atm) nor the intravenous anesthetic
agent pentobarbital (200 µM) had a significant effect on
rTASK currents (data not shown).
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Figure 6.
Concentration-response curve for bupivacaine.
Currents elicited by the 80 to +40 mV pulse have been normalized to
currents measured before and after bupivacaine application and fit to a logistic function (IC50 = 68 µM; Hill
coefficient = 0.6).
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Figure 7 illustrates the comparative
sensitivity of three of the five cloned tandem pore domain
K+ channels to various modulators. These data were
obtained from rTASK, ORK1, and TOK1 channels that were expressed in
parallel with the same batch of Xenopus oocytes by injection
of in vitro transcript and were exposed to the same
experimental conditions. rTASK was significantly more inhibited by
decreased extracellular pH and by local anesthetics than were the other
two channels, whereas ORK1 was significantly more inhibited by a
concentration of Zn2+ (100 µM) that
produced only moderate inhibition of TOK1 and rTASK.
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Figure 7.
Comparative pharmacology of tandem pore domain
K+ channels expressed in Xenopus
oocytes. Relative responses of three clones (rTASK, ORK1, and TOK1) are
compared for several potent modulators (extracellular pH 6.4, bupivacaine 1 mM, lidocaine 1 mM, and
Zn2+ 100 µM). Studies were performed
under two-electrode voltage clamp in frog Ringer's solution at pH 7.6. Response is defined as the current measured for the 80 to +40 mV
pulse during the treatment condition compared with control. Mean values
are shown with SE. Numbers over the bars
indicate number of experiments.
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Multiple regression was used to estimate  , the effective electrical
distance to the blocking site, according to a widely used model of
voltage-dependent binding (Woodhull, 1973). We found that pH and
Zn2+ inhibited rTASK currents in a voltage-dependent
manner, with = 0.16 ± 0.06 and 0.15 ± 0.04, respectively. These estimates suggest that H+ and
Zn2+ produce block at relatively peripheral sites in
the rTASK pore, both located at ~15% of the potential drop from the
membrane surface. However, bupivacaine inhibition was
voltage-independent at concentrations as high as 300 µM.
Regulation by intracellular phosphorylation
Because the primary amino acid sequence of rTASK possesses target
motifs for phosphorylation by PKA and PKC at the C terminal, we
investigated regulation of rTASK by these kinases. The PKC activators
phorbol 12,13-dibutyrate (PDBu; 500 nM) and phorbol 12-myristate 13-acetate (PMA; 50 nM) had no effect.
However, perfusion of rTASK-expressing oocytes with forskolin and
1-methyl-3-isobutylxanthine (IBMX), which increase intracellular cAMP
levels, reduced rTASK currents to 58% of control (Table 1). These
results suggest modulation of rTASK by PKA but not by PKC.
Single-channel properties
Excised outside-out patches from oocytes injected with rTASK
transcript showed noninactivating baseline channels that conducted outward currents at depolarized potentials (Fig.
8A). This pattern of
channel activity was not observed in saline-injected oocytes. Channel
activity did not appear to be altered by patch excision and did not
"run down". Inward currents were observed only at extremely
hyperpolarized potentials. These lower amplitude inward currents were
never observed in patches from saline-injected control oocytes or in
patches with no outward currents at positive potentials (n = 10). The single-channel currents were
well-resolved within the 2 kHz bandwidth of our recording system.
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Figure 8.
Patch-clamp recordings of rTASK currents expressed
in Xenopus oocytes. A, Unitary rTASK
currents recorded from an outside-out patch at several holding
potentials. The recording pipette was filled with 150 mM
K-aspartate, and the external solution was 150 mM NaCl.
Currents were filtered at 2 kHz. B, Compressed records of single rTASK channel activity.
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A compressed record of channel activity (Fig. 8B)
illustrates the pattern of spontaneous gating, which was characterized
by long-duration openings interrupted by short closures. Brief
interruptions of current often were present during openings at positive
potentials, which could be caused by a blocking ion or a result of the
intrinsic gating properties of the channel. rTASK currents were not
sensitive to changes in intracellular calcium (data not shown), unlike
the M channel (Selyanko and Brown, 1996).
Single-channel current-voltage relation
Figure 9A shows the
current-voltage relations of single rTASK channels recorded with an
outside-out patch configuration. Strong outward rectification was
evident when the patches were in a 150 mM NaCl bath
solution (circles). Under these conditions the
single-channel conductance at +20 mV was ~40 pS. Outward
rectification was reduced when external Na+ was
partially replaced with K+ (triangles),
whereas complete replacement with K+ shifted the
reversal potential to 0 mV and produced a linear I-V
relation with a conductance of ~14 pS (squares). The open probability of single rTASK channels did not exhibit any voltage dependence over a wide range of holding potentials (Fig.
9B). The mean open probability for potentials from 10 to
+70 mV was 0.52 ± 0.03 (mean ± SEM; n = 34).
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Figure 9.
rTASK single-channel properties recorded from
outside-out patches. A, Single-channel
I-V relations. The recordings were made with 150 mM K+ in the recording pipette and bath
solutions of 150 mM NaCl (circles; n = 7), a mixture of 75 mM
Na+ with 75 mM K+
(triangles; n = 2), and 150 mM K+ (squares;
n = 4). In the presence of symmetrical 150 mM K+, the I-V relation
was best fit to a linear function. Data in the other conditions were
fit with third degree polynomial functions, which illustrates the
pattern of outward rectification. The unitary current was measured as
the amplitude of the current from the closed channel level to a cursor
positioned in the center of the open channel noise. Error bars indicate
SD of the mean. B, Independence of the open probability
of single rTASK channels from the patch potential. The open
probabilities are the means from outside-out patches
(n = 4) recorded with a bath solution of 150 mM NaCl. Individual values were calculated by setting the
single-channel amplitude to unity and integrating records from 30 sec
data segments at each voltage. Error bars indicate SDs.
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DISCUSSION |
rTASK is a new mammalian member of the tandem pore domain
K+ channel family. Two structural subclasses have
been found within this family, one containing eight putative
transmembrane domains (TOK1) and another with four putative
transmembrane domains (TWIK-1, TREK-1, ORK1, and TASK). A large number
of putative tandem pore domain K+ channels have been
identified as part of the C. elegans genome project, making
it likely that many more homologous two-pore domain K+ channels will be found in the mammalian genome.
All of the putative C. elegans two-pore domain
K+ channels found thus far have four transmembrane
domains (Wei et al., 1996).
By Northern analysis, we found that rTASK is highly expressed in rat
heart with lower levels in lung and brain tissue. This pattern of
relative expression is opposite that seen with TWIK-1, where high
levels of TWIK-1 mRNA can be found in mouse brain but none in mouse
heart (Lesage et al., 1996b). A different pattern of expression is also
seen with human TASK, where high levels of expression are found in
human pancreas and placenta and where brain expression is much higher
than heart expression (Duprat et al., 1997). Explanation of these
species differences in the tissue distribution of tandem pore domain
K+ channels must await a better understanding of the
physiological role of these channels. The double and triple bands found
with the human Northern blots may indicate either splice variants or the presence of a closely related homolog.
TWIK-1 self-associates to form homodimers via a disulfide bridge
between subunits (Lesage et al., 1996c) involving cysteine residues
between M1 and P1. Injection of rTASK transcript alone into
Xenopus oocytes gives rise to functional
K+ channels, suggesting that rTASK channels are
homodimeric. rTASK does not have a homologous cysteine or any predicted
extracellular cysteine. Therefore, if rTASK forms a disulfide bridge,
it must involve cysteine residues currently designated intracellular or intramembranous.
rTASK expression in Xenopus oocytes produced relatively
large outward K+ currents at depolarized potentials.
rTASK currents were observed at all membrane potentials tested and
appeared to be noninactivating in the manner of a background or leak
K+ channel (Hodgkin and Huxley, 1952). These results
suggest that rTASK currents may contribute to determining the resting
potential of the cell. In addition, as EK became
more positive, inward currents through rTASK channels were
correspondingly shifted in a manner resembling the open rectifier
properties described previously for ORK1 (Goldstein et al., 1996) that
passes large inward currents at high extracellular
K+ concentrations. This characteristic distinguishes
ORK1 and rTASK from TOK1, which does not pass large inward currents
(Ketchum et al., 1995; Lesage et al., 1996a). ORK1 and rTASK also are
similar in that their activation occurs almost instantaneously, in
contrast with TOK1 that exhibits slower activation from a deep closed
state (Lesage et al., 1996a).
rTASK currents are highly sensitive to extracellular pH. Low
extracellular pH (6.0-6.4) completely inhibits rTASK
K+ currents, whereas high extracellular pH
potentiates them. The extracellular pH of the CNS is tightly regulated,
but there are both physiological and pathophysiological circumstances
in which the extracellular pH of the CNS changes (synaptic
transmission, cardiac arrest/global ischemia, seizures, and spontaneous
or mechanical changes in alveolar ventilation) (Dingledine et al.,
1990; Chesler and Kaila, 1992; Andrews et al., 1994). Inhibition of
rTASK channels by increased extracellular acidity could lead to
depolarization or produce changes in excitability. Potentiation of
rTASK currents by increased extracellular pH during hyperventilation
may have importance during ascent to altitude or during control of
increased intracranial pressure.
We observed inhibition of rTASK currents after treatment of oocytes
with DNP (Table 1). This suggests that rTASK is inhibited by
intracellular acidity. However, other consequences of DNP treatment (e.g., reduced intracellular ATP levels, which are known to modulate other potassium channels) may be responsible for this effect. In
addition, it is possible that DNP directly modulates rTASK.
The pH sensitivity of other tandem pore domain K+
channel clones has, to some extent, been investigated. Although TOK1
and TWIK-1 are inhibited by intracellular pH, TREK-1 is not (Fink et
al., 1996; Lesage et al., 1996a,b). TOK1 has been reported to be
insensitive to extracellular pH over a broad range (Lesage et al.,
1996a). In addition, many ATP-sensitive K+ channels
are inhibited by intracellular acidity (for review, see Traynelis,
1998).
Endogenous Zn2+ is synaptically released after
depolarization of neurons, with synaptic concentrations reaching as
high as 300 µM (Assaf and Chung, 1984; Howell et al.,
1984). We found that Zn2+ within that concentration
range significantly inhibited rTASK currents in a voltage-dependent
manner. Zn2+ modulates activity of many ligand-gated
and voltage-gated ion channels (Winegar and Lansman, 1990; Smart et
al., 1994) and can inhibit synaptic transmission in the hippocampus
(Xie and Smart, 1991). Although inhibition of voltage-gated potassium
channels by micromolar levels of extracellular Zn2+
has been reported (Harrison et al., 1993), our finding of
Zn2+ sensitivity of tandem pore domain
K+ channels is new.
rTASK is the first tandem pore domain K+ channel
cloned that contains a PSD95, disk-large, zo-1 (PDZ) domain binding
site at its C terminal (T/SXV), suggesting that rTASK may bind to PSD proteins. PSD proteins have been shown to localize to synapses with a
number of voltage-gated ion channels, including Kv1.1, Kv1.2, Kv1.4,
Kir 2.1, and Kir 2.3, as well as AMPA and NMDA receptors and neuronal
nitric oxide synthase (Kim et al., 1995; Kornau et al., 1995; Brenman
et al., 1996; Cohen et al., 1996; Dong et al., 1997). The presence of
this sequence in rTASK may indicate that it may colocalize with some of
these proteins as well. Interestingly, two important inhibitors of
rTASK, extracellular Zn2+ and acidity, also potently
inhibit some NMDA receptor combinations. By Northern analysis, the
highest expression of rTASK within the CNS is in the cerebellum.
However, the predominant NMDA receptor expressed in cerebellar granule
cells is the NR1/2C subtype, which is the least sensitive to
extracellular pH (Traynelis et al., 1995) and Zn2+
(Paoletti et al., 1997; Gray et al., in press). Thus,
Zn2+ and pH modulation of synaptic function in the
cerebellum may occur via rTASK and not NMDA receptors.
rTASK currents are sensitive to clinical concentrations of the local
anesthetics lidocaine and bupivacaine. Inhibition of rTASK by local
anesthetics could augment conduction blockade of peripheral nerves by
promoting formation of open and inactivated states of voltage-gated
sodium channels, making them more sensitive to local anesthetic block
(Ragsdale et al., 1994). Indeed, K+ channels similar
to rTASK (inhibition by extracellular and intracellular acidity,
sensitivity to Zn2+, inhibition by local
anesthetics) are expressed by thin myelinated nerves that convey
peripheral sensory inputs (Koh et al., 1992; Brau et al., 1995).
Inhibition of rTASK may contribute to the CNS (cerebellar and
vestibular) symptoms of local anesthetic, phenytoin, or quinidine
toxicity. Indeed, rTASK is inhibited by local anesthetics in the range
of levels associated with this toxicity (5-30 µM).
Intracellular protein kinases seem to produce important modulation of
tandem pore domain K+ channels. TOK1 and TWIK-1
currents are potentiated by activators of protein kinase C, whereas
TREK-1 currents are inhibited (Fink et al., 1996; Lesage et al.,
1996a,b). rTASK currents were not altered by the PKC activators PMA or
PDBu. Agents that increase intracellular cAMP levels, and thereby
activate protein kinase A, have no effect on TOK1 or TWIK-1 currents
but significantly inhibit both TREK-1 and rTASK currents (Fink et al.,
1996; Lesage et al., 1996a,b). Duprat et al. (1997) reported no effect
of forskolin and IBMX treatment on human TASK, whereas we observed
inhibition of rTASK. The discrepancy between the two results could be
related to clone specificity (human vs rat) or oocyte preparation
(possibly different cAMP levels and PKA activity).
In summary, we have cloned and expressed a new tandem pore domain
K+ channel from rat cerebellum. The open
rectification and open probability independent of voltage clearly
establishes rTASK as a baseline channel. Its primary sequence contains
a PDZ domain at its C terminal. Its function is regulated by pH,
Zn2+, local anesthetics, and activators of protein
kinase A. Further experiments will tell with which other cellular
proteins rTASK may colocalize and how such a complex may alter the
function of excitable tissues.
| |
FOOTNOTES |
Received Sept. 4, 1997; revised Nov. 12, 1997; accepted Nov. 13, 1997.
This research was supported by the University of California, San
Francisco, Research Evaluation and Allocation Committee Grant (A.T.G.),
National Institutes of Health Grants GMS-51372 (C.S.Y.) and GM-08440
(D.M.T.), and the Foundation for Anesthesia Education and Research
Young Investigator Award (C.S.Y.). We acknowledge Fang Chang for his
assistance in sequencing rTASK and Winifred von Ehrenburg for editorial
assistance. We also thank Dr. Steven Goldstein for his generous gift of
expression plasmids for ORK1 and TOK1.
D.L. and A.T.G. contributed equally to this work.
Correspondence should be addressed to Dr. C. Spencer Yost, Department
of Anesthesia, University of California San Francisco, 513 Parnassus
Avenue, S-261, Box 0542, San Francisco, CA 94143-0542.
| |
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S. Yun Cho, E. A. Beckett, S. A. Baker, I. Han, K. J. Park, K. Monaghan, S. M. Ward, K. M. Sanders, and S. D. Koh
A pH-sensitive potassium conductance (TASK) and its function in the murine gastrointestinal tract
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X. Bai, G. J Bugg, S. L Greenwood, J. D Glazier, C. P Sibley, P. N Baker, M. J Taggart, and G. K Fyfe
Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium
Reproduction,
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X. Bai, S. L. Greenwood, J. D. Glazier, P. N. Baker, C. P. Sibley, M. J. Taggart, and G. K. Fyfe
Localization of TASK and TREK, Two-Pore Domain K+ Channels, in Human Cytotrophoblast Cells
Reproductive Sciences,
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[Abstract]
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A. D O'Connell, M. J Morton, A. Sivaprasadarao, and M. Hunter
Selectivity and interactions of Ba2+ and Cs+ with wild-type and mutant TASK1 K+ channels expressed in Xenopus oocytes
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[Abstract]
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R. W. Putnam, J. A. Filosa, and N. A. Ritucci
Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons
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[Abstract]
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C. Liu, J. D. Au, H. L. Zou, J. F. Cotten, and C. S. Yost
Potent Activation of the Human Tandem Pore Domain K Channel TRESK with Clinical Concentrations of Volatile Anesthetics
Anesth. Analg.,
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[Abstract]
[Full Text]
[PDF]
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W. Lin, C. A. Burks, D. R. Hansen, S. C. Kinnamon, and T. A. Gilbertson
Taste Receptor Cells Express pH-Sensitive Leak K+ Channels
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C. E Clarke, E. L Veale, P. J Green, H. J Meadows, and A. Mathie
Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc
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[Abstract]
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M. Gruss, A. Mathie, W. R. Lieb, and N. P. Franks
The Two-Pore-Domain K+ Channels TREK-1 and TASK-3 Are Differentially Modulated by Copper and Zinc
Mol. Pharmacol.,
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S. C. M. Choisy, J. C. Hancox, L. A. Arberry, A. M. Reynolds, M. J. Shattock, and A. F. James
Evidence for a Novel K+ Channel Modulated by {alpha}1A-Adrenoceptors in Cardiac Myocytes
Mol. Pharmacol.,
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[Abstract]
[Full Text]
[PDF]
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A. P. Berg, E. M. Talley, J. P. Manger, and D. A. Bayliss
Motoneurons Express Heteromeric TWIK-Related Acid-Sensitive K+ (TASK) Channels Containing TASK-1 (KCNK3) and TASK-3 (KCNK9) Subunits
J. Neurosci.,
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[Full Text]
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I. M Fearon, M. Zhang, C. Vollmer, and C. A Nurse
GABA mediates autoreceptor feedback inhibition in the rat carotid body via presynaptic GABAB receptors and TASK-1
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[Abstract]
[Full Text]
[PDF]
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A.M. Gurney, O.N. Osipenko, D. MacMillan, K.M. McFarlane, R.J. Tate, and F.E.J. Kempsill
Two-Pore Domain K Channel, TASK-1, in Pulmonary Artery Smooth Muscle Cells
Circ. Res.,
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[Abstract]
[Full Text]
[PDF]
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I. P. de la Cruz, J. Z. Levin, C. Cummins, P. Anderson, and H. R. Horvitz
sup-9, sup-10, and unc-93 May Encode Components of a Two-Pore K+ Channel that Coordinates Muscle Contraction in Caenorhabditis elegans
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October 8, 2003;
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M. Zhang, I. M Fearon, H. Zhong, and C. A Nurse
Presynaptic modulation of rat arterial chemoreceptor function by 5-HT: role of K+ channel inhibition via protein kinase C
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September 15, 2003;
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I. Lauritzen, M. Zanzouri, E. Honore, F. Duprat, M. U. Ehrengruber, M. Lazdunski, and A. J. Patel
K+-dependent Cerebellar Granule Neuron Apoptosis: ROLE OF TASK LEAK K+ CHANNELS
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S. G. Meuth, T. Budde, T. Kanyshkova, T. Broicher, T. Munsch, and H.-C. Pape
Contribution of TWIK-Related Acid-Sensitive K+ Channel 1 (TASK1) and TASK3 Channels to the Control of Activity Modes in Thalamocortical Neurons
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C. H. Kindler, M. Paul, H. Zou, C. Liu, B. D. Winegar, A. T. Gray, and C. S. Yost
Amide Local Anesthetics Potently Inhibit the Human Tandem Pore Domain Background K+ Channel TASK-2 (KCNK5)
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D. A. Bayliss, J. E. Sirois, and E. M. Talley
The TASK Family: Two-Pore Domain Background K+ Channels
Mol. Interv.,
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V. A Campanucci, I. M Fearon, and C. A Nurse
A novel O2-sensing mechanism in rat glossopharyngeal neurones mediated by a halothane-inhibitable background K+ conductance
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W.-J. Shin and B. D. Winegar
Modulation of Noninactivating K+ Channels in Rat Cerebellar Granule Neurons by Halothane, Isoflurane, and Sevoflurane
Anesth. Analg.,
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E. M. Talley, J. E. Sirois, Q. Lei, and D. A. Bayliss
Two-Pore-Domain (Kcnk) Potassium Channels: Dynamic Roles in Neuronal Function
Neuroscientist,
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[Abstract]
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S. A. Jones, M. J. Morton, M. Hunter, and M. R. Boyett
Expression of TASK-1, a pH-sensitive twin-pore domain K+ channel, in rat myocytes
Am J Physiol Heart Circ Physiol,
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[Abstract]
[Full Text]
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J. E Sirois, C. Lynch III, and D. A Bayliss
Convergent and reciprocal modulation of a leak K+ current and Ih by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones
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[Abstract]
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[PDF]
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A. Barbuti, S. Ishii, T. Shimizu, R. B. Robinson, and S. J. Feinmark
Block of the background K+ channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor
Am J Physiol Heart Circ Physiol,
June 1, 2002;
282(6):
H2024 - H2030.
[Abstract]
[Full Text]
[PDF]
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E. M. Talley and D. A. Bayliss
Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) Potassium Channels. VOLATILE ANESTHETICS AND NEUROTRANSMITTERS SHARE A MOLECULAR SITE OF ACTION
J. Biol. Chem.,
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[Abstract]
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C. P. Washburn, J. E. Sirois, E. M. Talley, P. G. Guyenet, and D. A. Bayliss
Serotonergic Raphe Neurons Express TASK Channel Transcripts and a TASK-Like pH- and Halothane-Sensitive K+ Conductance
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M. I. Niemeyer, L. P. Cid, L. F. Barros, and F. V. Sepulveda
Modulation of the Two-pore Domain Acid-sensitive K+ Channel TASK-2 (KCNK5) by Changes in Cell Volume
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E. M. Talley, G. Solorzano, Q. Lei, D. Kim, and D. A. Bayliss
CNS Distribution of Members of the Two-Pore-Domain (KCNK) Potassium Channel Family
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October 1, 2001;
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A. Olschewski, H. Olschewski, M. E. Brau, G. Hempelmann, W. Vogel, and B. V. Safronov
Basic Electrical Properties of In situ Endothelial Cells of Small Pulmonary Arteries during Postnatal Development
Am. J. Respir. Cell Mol. Biol.,
September 1, 2001;
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[Abstract]
[Full Text]
[PDF]
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S.-C. Chuang, R. Bianchi, D. Kim, H.-S. Shin, and R. K. S. Wong
Group I Metabotropic Glutamate Receptors Elicit Epileptiform Discharges in the Hippocampus through PLC{beta}1 Signaling
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August 15, 2001;
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Y. A. Blednov, M. Stoffel, S. R. Chang, and R. A. Harris
Potassium Channels as Targets for Ethanol: Studies of G-Protein-Coupled Inwardly Rectifying Potassium Channel 2 (GIRK2) Null Mutant Mice
J. Pharmacol. Exp. Ther.,
August 1, 2001;
298(2):
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[Full Text]
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G. Czirjak, G. L. Petheo, A. Spat, and P. Enyedi
Inhibition of TASK-1 potassium channel by phospholipase C
Am J Physiol Cell Physiol,
August 1, 2001;
281(2):
C700 - C708.
[Abstract]
[Full Text]
[PDF]
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E. Vega-Saenz de Miera, D. H. P. Lau, M. Zhadina, D. Pountney, W. A. Coetzee, and B. Rudy
KT3.2 and KT3.3, Two Novel Human Two-Pore K+ Channels Closely Related to TASK-1
J Neurophysiol,
July 1, 2001;
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130 - 142.
[Abstract]
[Full Text]
[PDF]
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A.J. Patel and E. Honore
Molecular physiology of oxygen-sensitive potassium channels
Eur. Respir. J.,
July 1, 2001;
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221 - 227.
[Abstract]
[Full Text]
[PDF]
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D Leonoudakis, W Mailliard, K Wingerd, D Clegg, and C Vandenberg
Inward rectifier potassium channel Kir2.2 is associated with synapse-associated protein SAP97
J. Cell Sci.,
January 3, 2001;
114(5):
987 - 998.
[Abstract]
[PDF]
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D. F Boyd, J. A Millar, C. S Watkins, and A. Mathie
The role of Ca2+ stores in the muscarinic inhibition of the K+ current IK(SO) in neonatal rat cerebellar granule cells
J. Physiol.,
December 1, 2000;
529(2):
321 - 331.
[Abstract]
[Full Text]
[PDF]
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F. Lesage and M. Lazdunski
Molecular and functional properties of two-pore-domain potassium channels
Am J Physiol Renal Physiol,
November 1, 2000;
279(5):
F793 - F801.
[Abstract]
[Full Text]
[PDF]
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M. T. Kunkel, D. B. Johnstone, J. H. Thomas, and L. Salkoff
Mutants of a Temperature-Sensitive Two-P Domain Potassium Channel
J. Neurosci.,
October 15, 2000;
20(20):
7517 - 7524.
[Abstract]
[Full Text]
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J. E. Sirois, Q. Lei, E. M. Talley, C. Lynch III, and D. A. Bayliss
The TASK-1 Two-Pore Domain K+ Channel Is a Molecular Substrate for Neuronal Effects of Inhalation Anesthetics
J. Neurosci.,
September 1, 2000;
20(17):
6347 - 6354.
[Abstract]
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G. Czirják, T. Fischer, A. Spät, F. Lesage, and P. Enyedi
TASK (TWIK-Related Acid-Sensitive K+ Channel) Is Expressed in Glomerulosa Cells of Rat Adrenal Cortex and Inhibited by Angiotensin II
Mol. Endocrinol.,
June 1, 2000;
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863 - 874.
[Abstract]
[Full Text]
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K. J Buckler, B. A Williams, and E. Honore
An oxygen-, acid- and anaesthetic-sensitive TASK-like background potassium channel in rat arterial chemoreceptor cells
J. Physiol.,
May 15, 2000;
525(1):
135 - 142.
[Abstract]
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F. Maingret, A. J. Patel, F. Lesage, M. Lazdunski, and E. Honore
Lysophospholipids Open the Two-pore Domain Mechano-gated K+ Channels TREK-1 and TRAAK
J. Biol. Chem.,
March 31, 2000;
275(14):
10128 - 10133.
[Abstract]
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Y. Kim, H. Bang, and D. Kim
TASK-3, a New Member of the Tandem Pore K+ Channel Family
J. Biol. Chem.,
March 24, 2000;
275(13):
9340 - 9347.
[Abstract]
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[PDF]
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Y. Kim, H. Bang, and D. Kim
TBAK-1 and TASK-1, two-pore K+ channel subunits: kinetic properties and expression in rat heart
Am J Physiol Heart Circ Physiol,
November 1, 1999;
277(5):
H1669 - H1678.
[Abstract]
[Full Text]
[PDF]
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F. Maingret, A. J. Patel, F. Lesage, M. Lazdunski, and E. Honore
Mechano- or Acid Stimulation, Two Interactive Modes of Activation of the TREK-1 Potassium Channel
J. Biol. Chem.,
September 17, 1999;
274(38):
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[Abstract]
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H. S. Ghai and L. T. Buck
Acute reduction in whole cell conductance in anoxic turtle brain
Am J Physiol Regulatory Integrative Comp Physiol,
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[Abstract]
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M. Salinas, R. Reyes, F. Lesage, M. Fosset, C. Heurteaux, G. Romey, and M. Lazdunski
Cloning of a New Mouse Two-P Domain Channel Subunit and a Human Homologue with a Unique Pore Structure
J. Biol. Chem.,
April 23, 1999;
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R. A. Chavez, A. T. Gray, B. B. Zhao, C. H. Kindler, M. J. Mazurek, Y. Mehta, J. R. Forsayeth, and C. S. Yost
TWIK-2, a New Weak Inward Rectifying Member of the Tandem Pore Domain Potassium Channel Family
J. Biol. Chem.,
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R. Reyes, F. Duprat, F. Lesage, M. Fink, M. Salinas, N. Farman, and M. Lazdunski
Cloning and Expression of a Novel pH-sensitive Two Pore Domain K+ Channel from Human Kidney
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J. E Sirois, J. J Pancrazio, C. Lynch III, and D. A Bayliss
Multiple ionic mechanisms mediate inhibition of rat motoneurones by inhalation anaesthetics
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S. Rajan, E. Wischmeyer, G. Xin Liu, R. Preisig-Muller, J. Daut, A. Karschin, and C. Derst
TASK-3, a Novel Tandem Pore Domain Acid-sensitive K+ Channel. AN EXTRACELLULAR HISTIDINE AS pH SENSOR
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H. Bang, Y. Kim, and D. Kim
TREK-2, a New Member of the Mechanosensitive Tandem-pore K+ Channel Family
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C. M. B. Lopes, P. G. Gallagher, M. E. Buck, M. H. Butler, and S. A. N. Goldstein
Proton Block and Voltage Gating Are Potassium-dependent in the Cardiac Leak Channel Kcnk3
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F. Lesage, C. Terrenoire, G. Romey, and M. Lazdunski
Human TREK2, a 2P Domain Mechano-sensitive K+ Channel with Multiple Regulations by Polyunsaturated Fatty Acids, Lysophospholipids, and Gs, Gi, and Gq Protein-coupled Receptors
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A. J. Patel, F. Maingret, V. Magnone, M. Fosset, M. Lazdunski, and E. Honore
TWIK-2, an Inactivating 2P Domain K+ Channel
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S. Rajan, E. Wischmeyer, C. Karschin, R. Preisig-Muller, K.-H. Grzeschik, J. Daut, A. Karschin, and C. Derst
THIK-1 and THIK-2, a Novel Subfamily of Tandem Pore Domain K+ Channels
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M. E. Hartness, A. Lewis, G. J. Searle, I. O'Kelly, C. Peers, and P. J. Kemp
Combined Antisense and Pharmacological Approaches Implicate hTASK as an Airway O2 Sensing K+ Channel
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G. Czirjak and P. Enyedi
Formation of Functional Heterodimers between the TASK-1 and TASK-3 Two-pore Domain Potassium Channel Subunits
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J. A. Millar, L. Barratt, A. P. Southan, K. M. Page, R. E. W. Fyffe, B. Robertson, and A. Mathie
A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons
PNAS,
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A. Barbuti, S. Ishii, T. Shimizu, R. B. Robinson, and S. J. Feinmark
Block of the background K+ channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor
Am J Physiol Heart Circ Physiol,
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[Full Text]
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C. Terrenoire, I. Lauritzen, F. Lesage, G. Romey, and M. Lazdunski
A TREK-1-Like Potassium Channel in Atrial Cells Inhibited by {beta}-Adrenergic Stimulation and Activated by Volatile Anesthetics
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Top
Abstract
Introduction
