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 (Ba(2+), Co(2+), Ni(2+), Pb(2+), and Zn(2+)) were examined on TREK-2 expressed in Xenopus oocytes using the two-electrode voltage clamping technique. Pb(2+) inhibited TREK channel activity (IC(50) = 15.6 microM), whereas Zn(2+) enhanced it in a dose-dependent manner (EC(50) = 87.1 microM). Ba(2+) slightly inhibited TREK currents but only at high concentrations. Co(2+) and Ni(2+) had no significant effect. The structural element(s) contributing to the zinc enhancement effect were studied using a series of chimeras consisting of Zn(2+)-activated TREK-2 and Zn(2+)-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 Zn(2+) may be used as a criterion of TREK-2, distinguishing it from other two-pore K(+) channels.