Abstract
δ-Hexachlorocyclohexane (δ-HCH), a lipophilic neurodepressant agent, has been shown to inhibit neurotransmitter release and stimulate ryanodine-sensitive Ca2+ channels. However, the effect of δ-HCH on neuronal activity remains unclear, although it may enhance the γ-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, δ-HCH increased the amplitude of Ca2+-activated K+current (IK(Ca)). δ-HCH (100 μM) slightly inhibited the amplitude of voltage-dependent K+current. δ-HCH (30 μM) suppressed voltage-dependent L-type Ca2+ current (ICa, L), whereas γ-HCH (30 μM) had no effect on ICa, L. In the inside-out configuration, δ-HCH applied intracellularly did not change the single channel conductance of large conductance Ca2+-activated K+ (BKCa) channels; however, it did increase the channel activity. The δ-HCH-mediated increase in the channel activity is mainly mediated by its increase in the number of long-lived openings. δ-HCH reversibly increased the activity of BKCa channels in a concentration-dependent manner with an EC50 value of 20 μM. δ-HCH also caused a left shift in the midpoint for the voltage-dependent opening. In contrast, γ-HCH (30 μM) suppressed the activity of BKCachannels. Under the current-clamp mode, δ-HCH (30 μM) reduced the firing rate of spontaneous action potentials; however, γ-HCH (30 μM) increased it. In neuroblastoma IMR-32 cells, δ-HCH also increased the amplitude of IK(Ca) and stimulated the activity of intermediate-conductance KCachannels. This study provides evidence that δ-HCH is an opener of KCa channels. The effects of δ-HCH on these channels may partially, if not entirely, be responsible for the underlying cellular mechanisms by which δ-HCH affects neuronal or neuroendocrine function.
Footnotes
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Send reprint requests to: Dr. Sheng-Nan Wu, Department of Medical Education and Research, Veterans General Hospital-Kaohsiung, No. 386, Ta-Chung 1st Road, Kaohsiung City, Taiwan. E-mail:snwu{at}isca.vghks.gov.tw
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This study was aided by grants from the National Science Council (NSC-89-2320-B-075B-008) and the Veterans General Hospital-Kaohsiung (VGHKS-89-103), Taiwan, Republic of China.
- Abbreviations:
- HCH
- hexachlorocyclohexane
- GABA
- γ-aminobutyric acid
- IP3
- inositol 1,4,5-trisphosphate hexasodium
- IK(Ca)
- Ca2+-activated K+ current
- BKCa channel
- large conductance Ca2+-activated K+channel
- Received September 20, 1999.
- Accepted February 3, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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