TY - JOUR
T1 - The potent activation of Ca2+-activated K+ current by NVP-AUY922 in the human pancreatic duct cell line (PANC-1) possibly independent of heat shock protein 90 inhibition
AU - Chiang, Nai Jung
AU - Wu, Sheng Nan
AU - Chen, Li Tzong
N1 - Funding Information:
Declaration of funding interests: This work was funded in part by the National Science Council of Taiwan under contracts ( NSC-101-2320-B-006-009 and NSC-101-2815-C-006-082-B ).
Publisher Copyright:
© 2015 The Authors.
PY - 2015
Y1 - 2015
N2 - 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 Ca2+-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 Ca2+-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.
AB - 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 Ca2+-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 Ca2+-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.
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U2 - 10.1016/j.jphs.2015.02.009
DO - 10.1016/j.jphs.2015.02.009
M3 - Article
C2 - 25953267
AN - SCOPUS:84938511458
SN - 1347-8613
VL - 127
SP - 404
EP - 413
JO - Journal of Pharmacological Sciences
JF - Journal of Pharmacological Sciences
IS - 4
ER -