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

GV-58 ((2 R )-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.