Effectiveness in the inhibition of dapagliflozin and canagliflozin on M-type K⁺ current and α-methylglucoside-induced current in pituitary tumor (GH₃) and pheochromocytoma PC12 cells

Dapagliflozin (DAPA) or canagliflozin (CANA), Na⁺-dependent glucose co-transporter type 2 (SGLT2) inhibitors, were used for treatment of type II diabetes mellitus. Addition of DAPA or CANA suppressed M-type K⁺ current (I_K(M)) in pituitary tumor (GH₃) and pheochromocytoma PC12 cells. The IC₅₀ value for DAPA- or CANA-mediated inhibition of I_K(M) in GH₃ cells was 0.11 or 0.42 μM, respectively. The presence of DAPA (0.1 μM) shifted the steady-state activation of I_K(M) to less depolarized potential without changing the gating charge of the current. During high-frequency depolarizing pulses, I_K(M) magnitude was reduced by DAPA; however, DAPA-induced block of I_K(M) remained effective. The amplitude of neither erg-mediated K⁺ current nor hyperpolarization-activated cation current in GH₃ cells was modified in the presence of 1 μM DAPA. Alternatively, addition of DAPA, CANA, phlorizin or chlorotoxin effectively suppressed α-methylglucoside-(αMG-) induced current (I_αMG) in GH₃ cells, albeit inability of tefluthrin (activator of I_Na) to suppress this current. DAPA shifted the charge-voltage relation of presteady-state I_αMG in a rightward and downward direction with no change in the gating charge of the I_αMG. Under current-clamp recordings, subsequent additions of DAPA, but still in the continued presence of αMG, increased the firing rate of spontaneous action potentials stimulated by αMG. Our results suggested that activity of SGLT was expressed functionally in GH₃ and PC12 cells. Therefore, inhibitory actions of DAPA or CANA on the amplitude and gating of I_K(M) might provide a yet unidentified mechanism through which the SGLT1 or SGLT2 activity were attenuated in unclamped cells occurring in vivo.