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

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 (I_Na) 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⁺ (BK_Ca) channels were also studied. Key Results KMUP-1 depressed the transient and late components of I_Na with different potencies. The IC₅₀ values required for its inhibitory effect on transient and late I_Na were 22.5 and 1.8 μM respectively. KMUP-1 (3 μM) shifted the steady-state inactivation of I_Na to a hyperpolarized potential by -10 mV, despite inability to alter the recovery of I_Na from inactivation. In cell-attached configuration, KMUP-1 applied to bath increased BK_Ca-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 I_Na with a concomitant increase of current inactivation in HEKT293T cells expressing SCN5A. Conclusions and Implications Apart from activating BK_Ca channels, KMUP-1 preferentially suppresses late I_Na. The effects of KUMP-1 on ion currents presented here constitute an underlying ionic mechanism of its actions.