Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na+ and Ca2+-activated K+ currents in GH3 pituitary tumour cells

Yi Ching Lo, Yu Ting Tseng, Chi Ming Liu, Bin Nan Wu, Sheng-Nan Wu

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background and Purpose 7-[2-[4-(2-Chlorophenyl)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) is a xanthine-based derivative. It has soluble GC activation and K+-channel opening activity. Effects of this compound on ion currents in pituitary GH3 cells were investigated in this study. Experimental Approach The aim of this study was to evaluate effects of KMUP-1 on the amplitude and gating of voltage-gated Na+ current (INa) in pituitary GH3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca2+-activated K+ current and the activity of large-conductance Ca2+-activated K+ (BKCa) channels were also studied. Key Results KMUP-1 depressed the transient and late components of INa with different potencies. The IC50 values required for its inhibitory effect on transient and late INa were 22.5 and 1.8 μM respectively. KMUP-1 (3 μM) shifted the steady-state inactivation of INa to a hyperpolarized potential by -10 mV, despite inability to alter the recovery of INa from inactivation. In cell-attached configuration, KMUP-1 applied to bath increased BKCa-channel activity; however, in inside-out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP-1 decreased the peak INa with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A. Conclusions and Implications Apart from activating BKCa channels, KMUP-1 preferentially suppresses late INa. The effects of KUMP-1 on ion currents presented here constitute an underlying ionic mechanism of its actions.

Original languageEnglish
Pages (from-to)5110-5122
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number21
DOIs
Publication statusPublished - 2015 Nov 1

Fingerprint

Xanthine
Pituitary Neoplasms
Ions
Calcium-Activated Potassium Channels
Architectural Accessibility
Theophylline
KMUP 1
piperazine
Baths
Inhibitory Concentration 50

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

@article{477845379a92432094e95ae0399b8cf1,
title = "Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na+ and Ca2+-activated K+ currents in GH3 pituitary tumour cells",
abstract = "Background and Purpose 7-[2-[4-(2-Chlorophenyl)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) is a xanthine-based derivative. It has soluble GC activation and K+-channel opening activity. Effects of this compound on ion currents in pituitary GH3 cells were investigated in this study. Experimental Approach The aim of this study was to evaluate effects of KMUP-1 on the amplitude and gating of voltage-gated Na+ current (INa) in pituitary GH3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca2+-activated K+ current and the activity of large-conductance Ca2+-activated K+ (BKCa) channels were also studied. Key Results KMUP-1 depressed the transient and late components of INa with different potencies. The IC50 values required for its inhibitory effect on transient and late INa were 22.5 and 1.8 μM respectively. KMUP-1 (3 μM) shifted the steady-state inactivation of INa to a hyperpolarized potential by -10 mV, despite inability to alter the recovery of INa from inactivation. In cell-attached configuration, KMUP-1 applied to bath increased BKCa-channel activity; however, in inside-out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP-1 decreased the peak INa with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A. Conclusions and Implications Apart from activating BKCa channels, KMUP-1 preferentially suppresses late INa. The effects of KUMP-1 on ion currents presented here constitute an underlying ionic mechanism of its actions.",
author = "Lo, {Yi Ching} and Tseng, {Yu Ting} and Liu, {Chi Ming} and Wu, {Bin Nan} and Sheng-Nan Wu",
year = "2015",
month = "11",
day = "1",
doi = "10.1111/bph.13276",
language = "English",
volume = "172",
pages = "5110--5122",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "21",

}

Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na+ and Ca2+-activated K+ currents in GH3 pituitary tumour cells. / Lo, Yi Ching; Tseng, Yu Ting; Liu, Chi Ming; Wu, Bin Nan; Wu, Sheng-Nan.

In: British Journal of Pharmacology, Vol. 172, No. 21, 01.11.2015, p. 5110-5122.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na+ and Ca2+-activated K+ currents in GH3 pituitary tumour cells

AU - Lo, Yi Ching

AU - Tseng, Yu Ting

AU - Liu, Chi Ming

AU - Wu, Bin Nan

AU - Wu, Sheng-Nan

PY - 2015/11/1

Y1 - 2015/11/1

N2 - Background and Purpose 7-[2-[4-(2-Chlorophenyl)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) is a xanthine-based derivative. It has soluble GC activation and K+-channel opening activity. Effects of this compound on ion currents in pituitary GH3 cells were investigated in this study. Experimental Approach The aim of this study was to evaluate effects of KMUP-1 on the amplitude and gating of voltage-gated Na+ current (INa) in pituitary GH3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca2+-activated K+ current and the activity of large-conductance Ca2+-activated K+ (BKCa) channels were also studied. Key Results KMUP-1 depressed the transient and late components of INa with different potencies. The IC50 values required for its inhibitory effect on transient and late INa were 22.5 and 1.8 μM respectively. KMUP-1 (3 μM) shifted the steady-state inactivation of INa to a hyperpolarized potential by -10 mV, despite inability to alter the recovery of INa from inactivation. In cell-attached configuration, KMUP-1 applied to bath increased BKCa-channel activity; however, in inside-out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP-1 decreased the peak INa with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A. Conclusions and Implications Apart from activating BKCa channels, KMUP-1 preferentially suppresses late INa. The effects of KUMP-1 on ion currents presented here constitute an underlying ionic mechanism of its actions.

AB - Background and Purpose 7-[2-[4-(2-Chlorophenyl)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) is a xanthine-based derivative. It has soluble GC activation and K+-channel opening activity. Effects of this compound on ion currents in pituitary GH3 cells were investigated in this study. Experimental Approach The aim of this study was to evaluate effects of KMUP-1 on the amplitude and gating of voltage-gated Na+ current (INa) in pituitary GH3 cells and in HEKT293T cells expressing SCN5A. Both the amplitude of Ca2+-activated K+ current and the activity of large-conductance Ca2+-activated K+ (BKCa) channels were also studied. Key Results KMUP-1 depressed the transient and late components of INa with different potencies. The IC50 values required for its inhibitory effect on transient and late INa were 22.5 and 1.8 μM respectively. KMUP-1 (3 μM) shifted the steady-state inactivation of INa to a hyperpolarized potential by -10 mV, despite inability to alter the recovery of INa from inactivation. In cell-attached configuration, KMUP-1 applied to bath increased BKCa-channel activity; however, in inside-out patches, this compound applied to the intracellular surface had no effect on it. It prolonged the latency in the generation of action currents elicited by triangular voltage ramps. Additionally, KMUP-1 decreased the peak INa with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A. Conclusions and Implications Apart from activating BKCa channels, KMUP-1 preferentially suppresses late INa. The effects of KUMP-1 on ion currents presented here constitute an underlying ionic mechanism of its actions.

UR - http://www.scopus.com/inward/record.url?scp=84945955194&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84945955194&partnerID=8YFLogxK

U2 - 10.1111/bph.13276

DO - 10.1111/bph.13276

M3 - Article

C2 - 26276211

AN - SCOPUS:84945955194

VL - 172

SP - 5110

EP - 5122

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 21

ER -