Zinc activates TREK-2 potassium channel activity

TWIK-related K+ 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 (Ba2+, Co2+, Ni2+, Pb2+, and Zn2+) were examined on TREK-2 expressed in Xenopus oocytes using the two-electrode voltage clamping technique. Pb2+ inhibited TREK channel activity (IC50 = 15.6 mu M), whereas Zn2+ enhanced it in a dose-dependent manner (EC50 = 87.1 mu M). Ba2+ slightly inhibited TREK currents but only at high concentrations. Co2+ and Ni2+ had no significant effect. The structural contributing to the zinc enhancement effect were studied using a series of chimeras consisting of Zn2+- activated TREK-2 and Zn2+- inhibited TWIK-related acid-sensing K+ 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 Zn2+ may be used as a criterion of TREK-2, distinguishing it from other two-pore K+ channels.