Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na(+) and Ca(2+) -activated K(+) currents in GH3 pituitary tumour cells.
OBJECTIVE
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.


METHODS
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 Ca(2+) -activated K(+) current and the activity of large-conductance Ca(2+) -activated K(+) (BKCa ) channels were also studied.


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
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.
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yi-Ching
YC
Lo
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yu-Ting
YT
Tseng
Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan.
Chi-Ming
CM
Liu
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Bin-Nan
BN
Wu
Department of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan.|Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
Sheng-Nan
SN
Wu
D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D010911:Pituitary Neoplasms / Q000378:metabolism* / Q000473:pathology; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D014970:Xanthines / Q000494:pharmacology*
D010880:Piperidines; D015221:Potassium Channels; D014970:Xanthines; C439304:KMUP 1; D012964:Sodium; D002118:Calcium