Two-pore domain K+ channels—molecular sensors

O’Connell, Anthony; Morton, Michael J.; Hunter, Malcolm

doi:10.1016/s0005-2736(02)00597-7

Cited by 92 publications

(93 citation statements)

References 52 publications

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“…Predicted H þ dose-response curves indicate TASK-1, TASK-2 and TASK-3 channels are modulated by changes in pH between 8.4 and 6.4. Thus, TASK-1 is thought to be closed at pH 6.4, 50% open at pH 7.4 and 90% open at pH 8.4, while TASK-2 is thought to be closed at pH 6.4, 15% open at pH 7.4 and 50% open at pH 8.4 (O'Connell et al, 2002).…”

Section: Mj Gardener Et Almentioning

confidence: 99%

Functional evidence of a role for two‐pore domain potassium channels in rat mesenteric and pulmonary arteries

Gardener

Johnson

Burnham

et al. 2004

British J Pharmacology

131

123

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1 Experiments were performed to elucidate the mechanism by which alterations of extracellular pH (pH o ) change membrane potential (E M ) in rat mesenteric and pulmonary arteries. 2 Changing pH o from 7.4 to 6.4 or 8.4 produced a depolarisation or hyperpolarisation, respectively, in mesenteric and pulmonary arteries. Anandamide (10 mM) or bupivacaine (100 mM) reversed the hyperpolarisation associated with alkaline pH o , shifting the E M of both vessels to levels comparable to that at pH 6.4. In pulmonary arteries, clofilium (100 mM) caused a significant reversal of hyperpolarisation seen at pH 8.4 but was without effect at pH 7.4. 3 K þ channel blockade by 4-aminopyridine (4-AP) (5 mM), tetraethylammonium (TEA) (10 mM), Ba 2 þ (30 mM) and glibenclamide (10 mM) depolarised the pulmonary artery. However, shifts in E M with changes in pH o remained and were sensitive to anandamide (10 mM), bupivacaine (100 mM) or Zn 2 þ (200 mM). 4 Anandamide (0.3-60 mM) or bupivacaine (0.3-300 mM) caused a concentration-dependent increase in basal tone in pulmonary arteries. 5 RT-PCR demonstrated the expression of TASK-1, TASK-2, THIK-1, TRAAK, TREK-1, TWIK-1 and TWIK-2 in mesenteric arteries and TASK-1, TASK-2, THIK-1, TREK-2 and TWIK-2 in pulmonary arteries. TASK-1, TASK-2, TREK-1 and TWIK-2 protein was demonstrated in both arteries by immunostaining. 6 These experiments provide evidence for the presence of two-pore domain K þ channels in rat mesenteric and pulmonary arteries. Collectively, they strongly suggest that modulation of TASK-1 channels is most likely to have mediated the pH-induced changes in membrane potential observed in these vessels, and that blockade of these channels by anandamide or bupivacaine generates a small increase in pulmonary artery tone.

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Section: Mj Gardener Et Almentioning

confidence: 99%

Functional evidence of a role for two‐pore domain potassium channels in rat mesenteric and pulmonary arteries

Gardener

Johnson

Burnham

et al. 2004

British J Pharmacology

131

123

View full text Add to dashboard Cite

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“…It is becoming clear that the channel proteins underlying many of these leak K currents are members of the two-pore domain potassium (2-PK) channel family O'Connell et al, 2002;Lesage 2003). Currently, there are known to be at least 16 mammalian channels in the 2-PK channel family.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the human two‐pore domain potassium channel, TREK‐1, by fluoxetine and its metabolite norfluoxetine

Kennard

Chumbley

Ranatunga

et al. 2005

British J Pharmacology

175

159

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1 Block of the human two-pore domain potassium (2-PK) channel TREK-1 by fluoxetine (Prozac R ) and its active metabolite, norfluoxetine, was investigated using whole-cell patch-clamp recording of currents through recombinant channels in tsA 201 cells. 2 Fluoxetine produced a concentration-dependent inhibition of TREK-1 current that was reversible on wash. The IC 50 for block was 19 mM. Block by fluoxetine was voltage-independent. Fluoxetine (100 mM) produced an 84% inhibition of TREK-1 currents, but only a 31% block of currents through a related 2-PK channel, TASK-3. 3 Norfluoxetine was a more potent inhibitor of TREK-1 currents with an IC 50 of 9 mM. Block by norfluoxetine was also voltage-independent. 4 Truncation of the C-terminus of TREK-1 (D89) resulted in a loss of channel function, which could be restored by intracellular acidification or the mutation E306A. The mutation E306A alone increased basal TREK-1 current and resulted in a loss of the slow phase of TREK-1 activation. 5 Progressive deletion of the C-terminus of TREK-1 had no effect on the inhibition of the channel by fluoxetine. The E306A mutation, on the other hand, reduced the magnitude of fluoxetine inhibition, with 100 mM producing only a 40% inhibition. 6 It is concluded that fluoxetine and norfluoxetine are potent inhibitors of TREK-1. Block of TREK-1 by fluoxetine may have important consequences when the drug is used clinically in the treatment of depression.

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“…TASK channels have been localised to both electrically excitable and non-excitable tissues (e.g. brain, pancreas, lung and kidney; reviewed in O'Connell et al 2002). TREK channels have a predominantly neural location but their mRNA has also been found in small intestine, kidney and pancreas (Medhurst et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium

Bai¹,

Bugg²,

Greenwood³

et al. 2005

Reproduction

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Two-pore domain K 1 channels are an emerging family of K 1 channels that may contribute to setting membrane potential in both electrically excitable and non-excitable cells and, as such, influence cellular function. The human uteroplacental unit contains both excitable (e.g. myometrial) and non-excitable cells, whose function depends upon the activity of K 1 channels.We have therefore investigated the expression of two members of this family, TWIK (two-pore domain weak inward rectifying K 1 channel)-related acid-sensitive K 1 channel (TASK) and TWIK-related K 1 channel (TREK) in human myometrium. Using RT-PCR the mRNA expression of TASK and TREK isoforms was examined in myometrial tissue from pregnant women. mRNAs encoding TASK1, 4 and 5 and TREK1 were detected whereas weak or no signals were observed for TASK2, TASK3 and TREK2. Western blotting for TASK1 gave two bands of approximately 44 and 65 kDa, whereas TREK1 gave bands of approximately 59 and 90 kDa in myometrium from pregnant women. TASK1 and TREK1 immunofluorescence was prominent in intracellular and plasmalemmal locations within myometrial cells. Therefore, we conclude that the human myometrium is a site of expression for the two-pore domain K 1 channel proteins TASK1 and TREK1.Reproduction (

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Two-pore domain K+ channels—molecular sensors

Cited by 92 publications

References 52 publications

Functional evidence of a role for two‐pore domain potassium channels in rat mesenteric and pulmonary arteries

Functional evidence of a role for two‐pore domain potassium channels in rat mesenteric and pulmonary arteries

Inhibition of the human two‐pore domain potassium channel, TREK‐1, by fluoxetine and its metabolite norfluoxetine

Expression of TASK and TREK, two-pore domain K+ channels, in human myometrium

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