Zinc Activates TREK-2 Potassium Channel Activity

Abstract

TWIK-related Kϩ channel (TREK)-2 is thought to contribute to setting the resting membrane potential and to tuning action potential properties. In the present study, the effects of divalent metal ions (Ba 2ϩ , Co 2ϩ , Ni 2ϩ , Pb 2ϩ , and Zn 2ϩ ) were examined on TREK-2 expressed in Xenopus oocytes using the two-electrode voltage clamping technique. Pb 2ϩ inhibited TREK channel activity (IC 50 ϭ 15.6 M), whereas Zn 2ϩ enhanced it in a dose-dependent manner (EC 50 ϭ 87.1 M). Ba 2ϩ slightly inhibited TREK currents but only at high concentrations. Co 2ϩ and Ni 2ϩ had no significant effect. The structural element(s) contributing to the zinc enhancement effect were studied using a series of chimeras consisting of Zn 2ϩ -activated TREK-2 and Zn 2ϩ -inhibited TWIK-related acid-sensing K ϩ channel-3. The structural elements were localized to the first pore and the preceding extracellular loop of TREK-2, in which multiple residues, including His121, His156, Asp158, and Asn177, are likely to be involved in the zinc activation effect. Stimulation by Zn 2ϩ

Zinc and Mercuric Ions Distinguish TRESK from the Other Two-Pore-Domain K+Channels

“…However, TREK-1 was also activated identically in X. laevis oocytes, indicating that the two closely related TREK channels share the property of activation by zinc. Thus, our data do not support the conclusion of Kim et al (2005), that activation by zinc is specific for TREK-2 among the 2PK ϩ channels. Furthermore, considering the zinc resistance of human TREK-1 in HEK-293 cells (Gruss et al, 2004), it seems that the activation of TREK-1 by Zn 2ϩ depends on the examined species or the applied expression system.…”

“…Human TASK-3 was inhibited by zinc with IC 50 values of 12.7 and 19.8 M in HEK-293 cells and X. laevis oocytes, respectively (Clarke et al, 2004;Gruss et al, 2004). In turn, TREK-2 was activated by zinc in X. laevis oocytes with an EC 50 value of 87.1 M, and this activation was suggested to be a specific hallmark of TREK-2 among the 2PK ϩ channels (Kim et al, 2005). In this study, we performed the systematic analysis of zinc sensitivity of functional mouse 2PK ϩ channels.…”

The inhibitor of volume‐regulated anion channels DCPIB activates TREK potassium channels in cultured astrocytes

“…The comparison of the DCPIB-evoked current kinetics and DCPIB sensitivity in cultured rat cortical astrocytes and in TREK-transfected cells suggest that the DCPIB effect on K + conductance in astrocytes is most likely mediated by K2P 2.1 and K2P 10.1 channels. This view is further supported by the result that administration of Zn 2+ , which stimulates the activity of recombinant K2P 2.1 and K2P 10.1 (Gruss et al, 2004;Kim et al, 2005), promoted a small but nonsignificant increase of DCPIB current in cultured astrocytes. This observation also rules out the possibility that K2P 4.1, another member of the K2P channel family also activated by AA, contributes substantially to the DCPIB-induced K + current increase because K2P 4.1 is inhibited by Zn 2+ (Czirják and Enyedi, 2006).…”

“…In order to substantiate the observation that TREK channels were involved in the positive modulation of the K + conductance by DCPIB we investigated the effect of zinc ion (Zn 2+ ), which previous study indicated to be an activator of recombinant K2P 10.1 and K2P 2.1 (Gruss et al, 2004;Kim et al, 2005) and to inhibit the AA-activated K2P 4.1 (TRAAK) channel (Czirják and Enyedi, 2006). Micromolar concentrations of Zn 2+ (100 mM) had a negligible effect on basal K + current and caused a small non-significant increase in the outward current generated by submaximal concentrations of DCPIB (Supporting Information Figure S2).…”

Activation of TREK Currents by the Neuroprotective Agent Riluzole in Mouse Sympathetic Neurons

“…1, available at www.jneurosci.org as supplemental material). Most K2P channels are inhibited (TASK-3, TRAAK, TWIK-2, TRESK) or unaffected (THIK-1) by micromolar concentrations of zinc; only heterologously expressed TREK-1 (Czirják and Enyedi, 2006) and TREK-2 (Kim et al, 2005) are clearly activated by this ion. TASK-1 and TASK-2 were reported to be slightly inhibited , unaffected (Clarke et al, 2004), or slightly enhanced (Czirják and Enyedi, 2006) by zinc.…”