TY - JOUR
T1 - Concerted suppression of I h and activation of I K(M) by ivabradine, an HCN-channel inhibitor, in pituitary cells and hippocampal neurons
AU - Hsiao, Hung Tsung
AU - Liu, Yen Chin
AU - Liu, Ping Yen
AU - Wu, Sheng Nan
N1 - Funding Information:
This work is partly supported by National Cheng Kung University ( D106-35A13 , D107-F2519 and NCKUH-10709001 ), Tainan City, Taiwan. S.N.W received a Talent Award for the Outstanding Researchers from Ministry of Education, Taiwan. The authors would like to thank Huei-Ting Su and Kaissen Lee for technical assistances.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/7
Y1 - 2019/7
N2 - Ivabradine (IVA), a heart-rate reducing agent, is recognized as an inhibitor of hyperpolarization-activated cation current (I h ) and also reported to ameliorate inflammatory or neuropathic pain. However, to what extent this agent can perturb another types of membrane ion currents in neurons or endocrine cells remains to be largely unknown. Therefore, the I h or other types of ionic currents in pituitary tumor (GH 3 ) cells and in hippocampal mHippoE-14 neurons was studied with or without the presence of IVA or other related compounds. The IVA addition caused a time- and concentration-dependent reduction in the amplitude of I h with an IC 50 value of 0.64 μM and a K D value of 0.68 μM. IVA (0.3 μM) shifted the I h activation curve to a more negative potential by approximately 8 mV, despite no concomitant change in the gating charge. Additionally, IVA was found to increase M-type K + current (I K(M) ) together with a rightward shift in the activation curve. In cell-attached current recordings, IVA (3 μM) applied to the bath increased the open probability of M-type K + channels; however, it did not modify single-channel conductance of the channel. In current-clamp voltage recordings, IVA suppressed the firing of spontaneous action potentials in GH 3 cells; and, further addition of linopirdine attenuated its suppression of firing. In hippocampal mHippoE-14 neurons, IVA also effectively increased I K(M) amplitude. In summary, both inhibition of I h and activation of I K(M) caused by IVA can synergistically combine to influence electrical behaviors in different types of electrically excitable cells occurring in vivo.
AB - Ivabradine (IVA), a heart-rate reducing agent, is recognized as an inhibitor of hyperpolarization-activated cation current (I h ) and also reported to ameliorate inflammatory or neuropathic pain. However, to what extent this agent can perturb another types of membrane ion currents in neurons or endocrine cells remains to be largely unknown. Therefore, the I h or other types of ionic currents in pituitary tumor (GH 3 ) cells and in hippocampal mHippoE-14 neurons was studied with or without the presence of IVA or other related compounds. The IVA addition caused a time- and concentration-dependent reduction in the amplitude of I h with an IC 50 value of 0.64 μM and a K D value of 0.68 μM. IVA (0.3 μM) shifted the I h activation curve to a more negative potential by approximately 8 mV, despite no concomitant change in the gating charge. Additionally, IVA was found to increase M-type K + current (I K(M) ) together with a rightward shift in the activation curve. In cell-attached current recordings, IVA (3 μM) applied to the bath increased the open probability of M-type K + channels; however, it did not modify single-channel conductance of the channel. In current-clamp voltage recordings, IVA suppressed the firing of spontaneous action potentials in GH 3 cells; and, further addition of linopirdine attenuated its suppression of firing. In hippocampal mHippoE-14 neurons, IVA also effectively increased I K(M) amplitude. In summary, both inhibition of I h and activation of I K(M) caused by IVA can synergistically combine to influence electrical behaviors in different types of electrically excitable cells occurring in vivo.
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U2 - 10.1016/j.brainresbull.2019.03.016
DO - 10.1016/j.brainresbull.2019.03.016
M3 - Article
C2 - 30951796
AN - SCOPUS:85064119041
SN - 0361-9230
VL - 149
SP - 11
EP - 20
JO - Brain Research Bulletin
JF - Brain Research Bulletin
ER -