title: The potent activation of Ca(2+)-activated K(+) current by NVP-AUY922 in the human pancreatic duct cell line (PANC-1) possibly independent of heat shock protein 90 inhibition.
abstract: NVP-AUY922 (AUY) is a potent inhibitor of heat shock protein 90 (HSP90). Whether this compound can exert additional effects on membrane ion channels remains elusive. We investigated the effect of AUY on ion currents in human pancreatic duct epithelial cells (PDECs), including PANC-1 and MIA PaCa-2. AUY increased the amplitude of the K(+) current (IK) in PANC-1 cells shown by whole-cell configuration. Single-channel recordings revealed a large-conductance Ca(2+)-activated K(+) (BKCa) channel in PANC-1, but not in MIA PaCa-2. In cell-attached mode, AUY increased the probability of BKCa channel opening and also potentiated the activity of stretch-induced channels. However, other HSP inhibitors, 17-AAG or BIIB021 only slightly increased the activity of BKCa channels. In inside-out recordings, sodium hydrosulphide or caffeic acid phenethyl ester increased the activity of BKCa channels, but AUY did not. We further evaluated whether conductance of Ca(2+)-activated K(+) channels (IK(Ca)) influenced secretion of HCO3(-) and fluid in PDECs by using a modified Whitcomb-Ermentrout model. Simulation studies showed that an increase in IK(Ca) resulted in additional secretion of HCO3(-) and fluid by mimicking the effect of AUY in PDECs. Collectively, AUY can interact with the BKCa channel to largely increase IK(Ca) in PDECs.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, No. 367, Sheng Li Road, Tainan 70456, Taiwan; Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Shengli Road, Tainan 70456, Taiwan.
authors.forename: Nai-Jung
authors.initials: NJ
authors.lastname: Chiang
authors.affiliation: Department of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan 701, Taiwan; Institute of Basic Medical Sciences, National Cheng Kung University Medical College, No. 1, University Road, Tainan 701, Taiwan. Electronic address: snwu@mail.ncku.edu.tw.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Wu
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, No. 367, Sheng Li Road, Tainan 70456, Taiwan; Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, No. 138, Shengli Road, Tainan 70456, Taiwan. Electronic address: k153chen@gmail.com.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
mesh_terms: D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D010183:Pancreatic Ducts / Q000166:cytology* / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology*; D013268:Stimulation, Chemical
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D024681:Potassium Channels, Calcium-Activated; D012118:Resorcinols
keywords: AUY922; Ca(2+)-activated K(+) current; Heat shock protein 90; Large-conductance Ca(2+)-activated K(+) channel; Pancreatic duct epithelial cells