Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na+and Ca2+-activated K+currents in GH3pituitary 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.