Stimulatory effects of delta-hexachlorocyclohexane on Ca2+-activated K+ currents in GH(3) lactotrophs

delta-Hexachlorocyclohexane (delta-HCH), a lipophilic neurodepressant agent , has been shown to inhibit neurotransmitter release and stimulate ryanodin e-sensitive Ca2+ channels. However, the effect of delta-HCH on neuronal act ivity remains unclear, although it may enhance the gamma-aminobutyric acid- induced current. Its effects on ionic currents were investigated in rat pit uitary GH(3) cells and human neuroblastoma IMR-32 cells. In GH(3) cells, de lta-HCH increased the amplitude of Ca2+-activated K+ current (I-K(Ca)). del ta-HCH (100 mu M) slightly inhibited the amplitude of voltage-dependent Kcurrent. delta-HCH (30 mu M) suppressed voltage-dependent L-type Ca2+ curre nt (I-Ca,I- L), whereas gamma-HCH (30 mu M) had no effect on I-Ca,I- L. In the inside-out configuration, delta-HCH applied intracellularly did not cha nge the single channel conductance of large conductance Ca2+-activated K+ ( BKCa) channels; however, it did increase the channel activity. The delta-HC H-mediated increase in the channel activity is mainly mediated by its incre ase in the number of long-lived openings. delta-HCH reversibly increased th e activity of BKCa channels in a concentration-dependent manner with an EC5 0 value of 20 mu M. delta-HCH also caused a left shift in the midpoint for the voltage-dependent opening. In contrast, gamma-HCH (30 mu M) suppressed the activity of BKCa channels. Under the current-clamp mode, delta-HCH (30 mu M) reduced the firing rate of spontaneous action potentials; however, ga mma-HCH (30 mu M) increased it. In neuroblastoma IMR-32 cells, delta-HCH al so increased the amplitude of I-K(Ca) and stimulated the activity of interm ediate-conductance K-Ca channels. This study provides evidence that delta-H CH is an opener of K-Ca channels. The effects of delta-HCH on these channel s may partially, if not entirely, be responsible for the underlying cellula r mechanisms by which delta-HCH affects neuronal or neuroendocrine function .