Potentiation of Nicotine-Induced Currents by QO58, a Kv7 Channel Opener, in Intracardiac Ganglion Neurons of Rats.

Abstract

QO58 (5-(2,6-dichloro-5-fluoropyridin-3-yl)-3-phenyl-2-(trifluoromethyl)-1H-[1,5-a] pyrimidin-7-one) is currently used as a specific activator of the Kv7 (KCNQ) family of K⁺ channels. Here, we report an unexpected potentiating effect of this drug on nicotinic acetylcholine receptors. We recorded the whole-cell responses to the rapid application of nicotine with the Cs⁺-based pipette solution in intracardiac ganglion neurons freshly dissociated from the rat heart. Nicotine-induced inward currents were concentration-dependently blocked by mecamylamine, but not by 1 μM atropine at a holding potential of -60 mV. While the application of QO58 per se evoked a persistent inward current at this holding potential, 10 μM QO58 potentiated the peak amplitude of the nicotine-induced current. The QO58-induced inward currents were inhibited by the Kv7 channel blockers XE991 and Ba²⁺, but not by mecamylamine. On the other hand, the nicotine-induced current potentiated by QO58 was fully inhibited by mecamylamine. The facilitatory action of QO58 on the nicotinic response was unaffected by Ba²⁺. QO58 did not affect the reversal potential of the nicotine-induced current. QO58 apparently shifted the concentration-response curve of nicotine to the left. The half-maximal effective concentrations for nicotine in the absence and presence of 10 μM QO58 were 10.2 and 4.3 μM, respectively. These results suggest that QO58 acts as a positive allosteric modulator of nicotinic acetylcholine receptors. Given the prevalence of nicotinic receptor signaling, the present observations should be considered in future studies on the roles of Kv7 channels in the function of neural circuits and diseases.