Vol. 57, Issue 5, 865-874, May 2000

Stimulatory Effects of -Hexachlorocyclohexane on Ca²⁺-Activated K⁺ Currents in GH₃ Lactotrophs

Sheng-Nan Wu, Hui-Fang Li, and Hung-Ting Chiang

Departments of Medical Education and Research (S.-N.W., H.-F.L.) and Internal Medicine (H.-T.C.), Veterans General Hospital, Kaohsiung, Taiwan, Republic of China

-Hexachlorocyclohexane (-HCH), a lipophilic neurodepressant agent, has been shown to inhibit neurotransmitter release and stimulate ryanodine-sensitive Ca²⁺ channels. However, the effect of -HCH on neuronal activity remains unclear, although it may enhance the -aminobutyric acid-induced current. Its effects on ionic currents were investigated in rat pituitary GH₃ cells and human neuroblastoma IMR-32 cells. In GH₃ cells, -HCH increased the amplitude of Ca²⁺-activated K⁺ current (I_K(Ca)). -HCH (100 µM) slightly inhibited the amplitude of voltage-dependent K⁺ current. -HCH (30 µM) suppressed voltage-dependent L-type Ca²⁺ current (I_{Ca, L}), whereas -HCH (30 µM) had no effect on I_{Ca, L}. In the inside-out configuration, -HCH applied intracellularly did not change the single channel conductance of large conductance Ca²⁺-activated K⁺ (BK_Ca) channels; however, it did increase the channel activity. The -HCH-mediated increase in the channel activity is mainly mediated by its increase in the number of long-lived openings. -HCH reversibly increased the activity of BK_Ca channels in a concentration-dependent manner with an EC₅₀ value of 20 µM. -HCH also caused a left shift in the midpoint for the voltage-dependent opening. In contrast, -HCH (30 µM) suppressed the activity of BK_Ca channels. Under the current-clamp mode, -HCH (30 µM) reduced the firing rate of spontaneous action potentials; however, -HCH (30 µM) increased it. In neuroblastoma IMR-32 cells, -HCH also increased the amplitude of I_K(Ca) and stimulated the activity of intermediate-conductance K_Ca channels. This study provides evidence that -HCH is an opener of K_Ca channels. The effects of -HCH on these channels may partially, if not entirely, be responsible for the underlying cellular mechanisms by which -HCH affects neuronal or neuroendocrine function.