Stimulatory effects of delta-hexachlorocyclohexane on Ca(2+)-activated K(+) currents in GH(3) lactotrophs.
delta-Hexachlorocyclohexane (delta-HCH), a lipophilic neurodepressant agent, has been shown to inhibit neurotransmitter release and stimulate ryanodine-sensitive Ca(2+) channels. However, the effect of delta-HCH on neuronal activity remains unclear, although it may enhance the gamma-aminobutyric acid-induced current. Its effects on ionic currents were investigated in rat pituitary GH(3) cells and human neuroblastoma IMR-32 cells. In GH(3) cells, delta-HCH increased the amplitude of Ca(2+)-activated K(+) current (I(K(Ca))). delta-HCH (100 microM) slightly inhibited the amplitude of voltage-dependent K(+) current. delta-HCH (30 microM) suppressed voltage-dependent L-type Ca(2+) current (I(Ca, L)), whereas gamma-HCH (30 microM) had no effect on I(Ca, L). In the inside-out configuration, delta-HCH applied intracellularly did not change the single channel conductance of large conductance Ca(2+)-activated K(+) (BK(Ca)) channels; however, it did increase the channel activity. The delta-HCH-mediated increase in the channel activity is mainly mediated by its increase in the number of long-lived openings. delta-HCH reversibly increased the activity of BK(Ca) channels in a concentration-dependent manner with an EC(50) value of 20 microM. delta-HCH also caused a left shift in the midpoint for the voltage-dependent opening. In contrast, gamma-HCH (30 microM) suppressed the activity of BK(Ca) channels. Under the current-clamp mode, delta-HCH (30 microM) reduced the firing rate of spontaneous action potentials; however, gamma-HCH (30 microM) increased it. In neuroblastoma IMR-32 cells, delta-HCH also increased the amplitude of I(K(Ca)) and stimulated the activity of intermediate-conductance K(Ca) channels. This study provides evidence that delta-HCH is an opener of K(Ca) channels. The effects of delta-HCH on these channels may partially, if not entirely, be responsible for the underlying cellular mechanisms by which delta-HCH affects neuronal or neuroendocrine function.
Wu
S N
SN
Department of Medical Education and Research, Veterans General Hospital, Kaohsiung, Taiwan, Republic of China. snwu@isca.vghks.gov.tw
Li
H F
HF
Chiang
H T
HT
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003620:Dantrolene / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004958:Estradiol / Q000494:pharmacology; D001556:Hexachlorocyclohexane / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D007700:Kinetics; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009447:Neuroblastoma; D010902:Pituitary Gland / Q000166:cytology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D051381:Rats; D012428:Ruthenium / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002492:Central Nervous System Depressants; D007211:Indoles; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D012433:Ryanodine; C086916:delta-hexachlorocyclohexane; C048220:paxilline; D004958:Estradiol; D001556:Hexachlorocyclohexane; D012428:Ruthenium; D015544:Inositol 1,4,5-Trisphosphate; D003620:Dantrolene; D002118:Calcium