Enhanced activity of Ca2+-activated K+ channels by 1-[2-hydroxy-3-propyl-4-[(1H-tetrazol-5-yl)butoxyl]phenyl] ethanone (LY-171883) in neuroendocrine and neuroblastoma cell lines.
The effects of LY-171883, an orally active leukotriene antagonist, on membrane currents were examined in pituitary GH(3) and in neuroblastoma IMR-32 cells. In GH(3) cells, LY-171883 (1-300 microM) reversibly increased the amplitude of Ca(2+)-activated K(+) current in a concentration-dependent manner with an EC(50) value of 15 microM. In excised inside-out patches recorded from GH(3) cells, the application of LY-171883 into cytosolic face did not modify single channel conductance of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels; however, it did increase the channel activity. The LY-171883-stimulated activity of BK(Ca) channels is dependent on membrane potential, and results mainly from an increase in mean open time and a decrease in mean closed time. However, REV-5901 (30 microM) suppressed the activity of BK(Ca) channels and MK-571 (30 microM) did not have any effect on it. Under the current-clamp condition, LY-171883 (30 microM) caused membrane hyperpolarization as well as decreased the firing rate of action potentials in GH(3) cells. In neuroblastoma IMR-32 cells, the application of LY-171883 (30 microM) also stimulated BK(Ca) channel activity in a voltage-dependent manner. However, neither clofibrate (30 microM) nor leukotriene D(4) (10 microM) affected the channel activity in IMR-32 cells. Troglitazone (30 microM) decreased the channel activity, but ciglitazone (30 microM) enhanced it. This study clearly demonstrates that LY-171883 stimulates the activity of BK(Ca) channels in a manner unlikely to be linked to its blockade of leukotriene receptors or stimulation of peroxisome proliferator-activated receptors. The stimulatory effects on these channels may, at least in part, contribute to the underlying cellular mechanisms by which LY-171883 affects neuronal or neuroendocrine function.
Department of Biological Science, National Sun Yat-Sen University, Kaohsiung, Taiwan, Republic of China.
Ping-Chia
PC
Li
Jin-Tung
JT
Liang
Hung-Tu
HT
Huang
Pei-Hsuan
PH
Lin
Sheng-Nan
SN
Wu
D000098:Acetophenones / Q000494:pharmacology*; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D004594:Electrophysiology; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017998:Leukotriene D4 / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma; D018408:Patch-Clamp Techniques; D010911:Pituitary Neoplasms; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects* / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D013777:Tetrazoles / Q000494:pharmacology*; D014357:Trypsin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000098:Acetophenones; D051036:Large-Conductance Calcium-Activated Potassium Channels; D020024:Leukotriene Antagonists; D024681:Potassium Channels, Calcium-Activated; D011422:Propionates; D011804:Quinolines; D013777:Tetrazoles; C049740:alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol; C059141:verlukast; D017998:Leukotriene D4; C044660:LY 171883; D014357:Trypsin