Evaluation of gambierol and its analogs for their inhibition of human Kv1.2 and cytotoxicity

Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel Kv1.2 (hKv1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from −80 mV to 40 mV. The IC50 values for the three compounds were 0.75 ± 0.15 nM, 7.6 ± 1.2 nM, and 28 ± 4.0 nM (the mean ± SEM, n = 3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hKv1.2. The IC50 values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild-type CHO cells were 95 ± 7.1 μM, 6.5 ± 0.8 μM (the mean ± SEM, n = 3), and >100 μM (n = 3), respectively, whereas those in the CHO cells stably expressing hKv1.2 were 78 ± 5.8 μM, 6.0 ± 1.0 μM (the mean ± SEM, n = 3), and >100 μM (n = 3). These results suggested that cytotoxicity is not triggered by inhibition of the human Kv1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose-dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells.

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