The two-pore-domain K(+) channels TREK-1 and TASK-3 are differentially modulated by copper and zinc

The "trace" elements copper and zinc are essential for life, and their role in the function of metalloproteins is well known. However, mounting evidence shows that these metals are also capable of modulating neuronal excitability under normal physiological conditions. They are present at high levels in the brain, are concentrated at nerve terminals, and are released at micromolar concentrations into the synaptic cleft after depolarization. They have been shown to affect the function of a number of different voltage- and ligand-gated ion channels, but their most important targets in the nervous system remain uncertain. In this study, we show that the two-pore-domain potassium channels TREK-1 and TASK-3 are potently modulated by both copper and zinc. Copper activates TREK-1 channels by 83 +/- 11% with an EC(50) of 3.0 +/- 1.0 microM, whereas TASK-3 channels are potently inhibited, with an IC(50) of 2.7 +/- 0.4 microM. Zinc inhibits both channels but with very different affinities. The IC(50) for inhibition of TREK-1 channels is 659 +/- 94 microM whereas the IC(50) for inhibition of TASK-3 is 12.7 +/- 1.0 microM. Using site-directed mutagenesis, we show that Asp128 plays a critical role in the copper activation of TREK-1. These observations provide a novel explanation for how copper and zinc might affect neuronal excitability under both normal physiological conditions, as well as during diseases in which copper or zinc homeostasis has been disrupted.