Activation of Voltage-Gated Na⁺ Current by GV-58, a Known Activator of Ca_V Channels

GV-58 ((2R)-2-[(6-{[(5-methylthiophen-2-yl)methyl]amino}-9-propyl-9H-purin-2-yl)amino] butan-1-ol) is recognized to be an activator of N-and P/Q-type Ca²⁺ currents. However, its modula-tory actions on other types of ionic currents in electrically excitable cells remain largely unanswered. This study was undertaken to explore the possible modifications caused by GV-58 in ionic currents (e.g., voltage-gated Na⁺ current [I_Na ], A-type K⁺ current [I_K(A) ], and erg-mediated K⁺ current [I_K(erg) ]) identified from pituitary GH₃ lactotrophs. GH₃ cell exposure to GV-58 enhanced the transient and late components of I_Na with varying potencies; consequently, the EC₅₀ values of GV-58 required for its differential increase in peak and late I_Na in GH₃ cells were estimated to be 8.9 and 2.6 µM, respectively. The I_Na in response to brief depolarizing pulse was respectively stimulated or sup-pressed by GV-58 or tetrodotoxin, but it failed to be altered by ω-conotoxin MVIID. Cell exposure to this compound increased the recovery of I_Na inactivation evoked by two-pulse protocol based on a geometrics progression; however, in its presence, there was a slowing in the inactivation rate of current decay evoked by a train of depolarizing pulses. The existence of GV-58 also resulted in an increase in the amplitude of ramp-induced resurgent and window I_Na . The presence of this compound inhibited I_K(A) magnitude, accompanied by a shortening in inactivation time course of the current; however, it mildly decreased I_K(erg) . Under current-clamp conditions, GV-58 increased the frequency of spontaneous action potentials in GH₃ cells. Moreover, in NSC-34 motor neuron-like cells, the presence of GV-58 not only raised I_Na amplitude but also reduced current inactivation. Taken together, the overall work provides a noticeable yet unidentified finding which implies that, in addition to its agonistic effect on Ca²⁺ currents, GV-58 may concertedly modify the amplitude and gating kinetics of I_Na in electrically excitable cells, hence modifiying functional activities in these cells.