TWIK-2, a New Weak Inward Rectifying Member of the Tandem Pore Domain Potassium Channel Family

Chavez, Raymond A.; Gray, Andrew T.; Zhao, Byron; Kindler, Christoph; Mazurek, Matthew J.; Mehta, Yash; Forsayeth, John; Yost, C. Spencer

doi:10.1074/jbc.274.12.7887

Cited by 128 publications

(107 citation statements)

References 28 publications

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“…In both channels, the effect is due to a change in the open probability of the channel. Human TWIK-1 and TWIK-2 are activated by the application of PMA when expressed in oocytes (20,21). There does not appear to be any change in the single channel conductance.…”

Section: Discussionmentioning

confidence: 99%

Activation of Protein Kinase C ϵ Inhibits the Two-pore Domain K+ Channel, TASK-1, Inducing Repolarization Abnormalities in Cardiac Ventricular Myocytes

Besana

Barbuti

Tateyama

et al. 2004

Journal of Biological Chemistry

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Activation of the platelet-activating factor (PAF) receptor leads to a decrease in outward current in murine ventricular myocytes by inhibiting the TASK-1 channel. TASK-1 carries a background or "leak" current and is a member of the two-pore domain potassium channel family. Its inhibition is sufficient to delay repolarization, causing prolongation of the action potential duration, and in some cases, early after depolarizations. We set out to determine the cellular mechanisms that control regulation of TASK-1 by PAF. Inhibition of TASK-1 via activation of the PAF receptor is protein kinase C (PKC)-dependent. Using isoform-specific PKC inhibitor or activator peptides in patch clamp experiments, we now demonstrate that activation of PKC⑀ is both necessary and sufficient to regulate murine TASK-1 current in a heterologous expression system and to induce repolarization abnormalities in isolated myocytes. Furthermore, site-directed mutagenesis studies have identified threonine 381, in the C-terminal tail of murine TASK-1, as a critical residue in this regulation.Regulation of cardiac function depends on the appropriate cumulative activity of numerous ion channels in individual cardiomyocytes that are responsible for the sequential depolarization-repolarization cycle known as the action potential (AP). 1 Although the major currents contributing to the AP have been described (1), additional small currents at specific points of low conductance in the AP cycle are sufficient to induce repolarization abnormalities in isolated cells (2, 3) and therefore arrhythmias in situ. These arrhythmias may contribute to the electrical abnormalities that lead to sudden death after myocardial infarction, which persists as the number one cause of death in the United States. We have focused on one channel that has been proposed to contribute to cardiac arrhythmias, TASK-1, a member of the recently described family of two-pore domain potassium channels (4).The two-pore domain K channel family is composed of at least 15 different members. These channels are widely distributed in excitable tissue, primarily in the brain and heart, and in general are responsive to environmental cues such as temperature, pH, and stretch (5, 6). Several are also regulated by lipids such as arachidonic acid or platelet-activating factor (PAF) (7-9). PAF is an inflammatory phospholipid that has been linked to arrhythmogensis in isolated canine ventricular myocytes (10). We have recently shown that PAF regulates the TASK-1 channel and determined that the arrhythmogenic effect of the stable PAF analog, carbamyl-platelet-activating factor (C-PAF) in mouse cardiomyocytes, is due to the inhibition of TASK-1 current in a protein kinase C (PKC)-dependent manner (2).In this study, we elucidate the molecular mechanism of the C-PAF effect on TASK-1 current by identifying the ⑀ isoform of PKC (PKC⑀) as a critical component in PAFR signaling. In addition, using site-directed mutagenesis, we have tentatively identified the critical residue that is the target for PKC in the mu...

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Section: Discussionmentioning

confidence: 99%

Activation of Protein Kinase C ϵ Inhibits the Two-pore Domain K+ Channel, TASK-1, Inducing Repolarization Abnormalities in Cardiac Ventricular Myocytes

Besana

Barbuti

Tateyama

et al. 2004

Journal of Biological Chemistry

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“…TWIK-1 is blocked by Ba 2ϩ , quinine, and quinidine (8). Recently, hTWIK-2 (also called hTOSS), a TWIK-1-related gene, was cloned by two independent groups (1,9). Although both hTWIK-2 and hTOSS sequences are identical, conflicting results were published concerning functional expression in heterologous systems (1,9).…”

mentioning

confidence: 96%

“…Recently, hTWIK-2 (also called hTOSS), a TWIK-1-related gene, was cloned by two independent groups (1,9). Although both hTWIK-2 and hTOSS sequences are identical, conflicting results were published concerning functional expression in heterologous systems (1,9). hTWIK-2 expressed in Xenopus oocytes was shown to be a noninactivating, time-independent, weak inward rectifier with biophysical properties identical to TWIK-1 (1).…”

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confidence: 99%

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TWIK-2, an Inactivating 2P Domain K+ Channel

Patel

Maingret

Magnone

et al. 2000

Journal of Biological Chemistry

104

111

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We cloned human and rat TWIK-2 and expressed this novel 2P domain K ؉ channel in transiently transfected COS cells. TWIK-2 is highly expressed in the gastrointestinal tract, the vasculature, and the immune system. Rat TWIK-2 currents are about 15 times larger than human TWIK-2 currents, but both exhibit outward rectification in a physiological K ؉ gradient and mild inward rectification in symmetrical K ؉ conditions. TWIK-2 currents are inactivating at depolarized potentials, and the kinetic of inactivation is highly temperature-sensitive. TWIK-2 shows an extremely low conductance, which prevents the visualization of discrete single channel events. The inactivation and rectification are intrinsic properties of TWIK-2 channels. In a physiological K ؉ gradient, TWIK-2 is half inhibited by 0.1 mM Ba 2؉ , quinine, and quinidine. Finally, cysteine 53 in the M1P1 external loop is required for functional expression of TWIK-2 but is not critical for subunit self-assembly. TWIK-2 is the first reported 2P domain K ؉ channel that inactivates. The base-line, transient, and delayed activities of TWIK-2 suggest that this novel 2P domain K ؉ channel may play an important functional role in cell electrogenesis.

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“…KCNK7 belongs to the inward rectifier subfamily of K 2P channels. It is most homologous to two other K 2P channels, TWIK-1 and TWIK-2, that are expressed in the cerebral circulation [1] cortex and hippocampus [3,12]. KCNK7 is also expressed in relatively high abundance in the cerebral cortex, hippocampus, nucleus accumbens and spinal cord [18].…”

Section: Introductionmentioning

confidence: 99%

Knockout of the gene encoding the K2P channel KCNK7 does not alter volatile anesthetic sensitivity

Yost¹,

Oh²,

Eger³

et al. 2008

Behavioural Brain Research

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The molecular site of action for volatile anesthetics remains unknown despite many years of study. Members of the K 2P potassium channel family, whose currents are potentiated by volatile anesthetics have emerged as possible anesthetic targets. In fact, a mouse model in which the gene for TREK-1 (KCNK2) has been inactivated shows resistance to volatile anesthetics. In this study we tested whether inactivation of another member of this ion channel family, KCNK7, in a knockout mouse displayed altered sensitivity to the anesthetizing effect of volatile anesthetics.KCNK7 knockout mice were produced by standard gene inactivation methods. Heterozygous breeding pairs produced animals that were homozygous, heterozygous or wildtype for the inactivated gene. Knockout animals were tested for movement in response to noxious stimulus (tail clamp) under varying concentrations of isoflurane, sevoflurane and desflurane to define the minimum alveolar concentration (MAC) preventing movement.Mice homozygous for inactivated KCNK7 were viable and indistinguishable in weight, general development and behavior from heterozygotes or wildtype littermates. Knockout mice (KCNK7 −/ −) displayed no difference in MAC for the three volatile anesthetics compared to heterozygous (+/ −) or wildtype (+/+) littermates.Because inactivation of KCNK7 does not alter MAC, KCNK7 may play only a minor role in normal CNS function or may have had its function compensated for by other inhibitory mechanisms. Additional studies with transgenic animals will help define the overall role of the K 2P channels in normal neurophysiology and in volatile anesthetic mechanisms.

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TWIK-2, a New Weak Inward Rectifying Member of the Tandem Pore Domain Potassium Channel Family

Cited by 128 publications

References 28 publications

Activation of Protein Kinase C ϵ Inhibits the Two-pore Domain K+ Channel, TASK-1, Inducing Repolarization Abnormalities in Cardiac Ventricular Myocytes

Activation of Protein Kinase C ϵ Inhibits the Two-pore Domain K+ Channel, TASK-1, Inducing Repolarization Abnormalities in Cardiac Ventricular Myocytes

TWIK-2, an Inactivating 2P Domain K+ Channel

Knockout of the gene encoding the K2P channel KCNK7 does not alter volatile anesthetic sensitivity

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