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 Ca(2+) currents. However, its modulatory 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 GH(3) lactotrophs. GH(3) cell exposure to GV-58 enhanced the transient and late components of I(Na) with varying potencies; consequently, the EC(50) values of GV-58 required for its differential increase in peak and late I(Na) in GH(3) 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 suppressed 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 GH(3) 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 Ca(2+) 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.