Multiple regulatory actions of 2-guanidine-4-methylquinazoline (GMQ), an agonist of acid-sensing ion channel type 3, on ionic currents in pituitary GH3 cells and in olfactory sensory (Rolf B1.T) neurons

GMQ (2-guanidine-4-methylquinazoline or N-(4-methyl-2-quinazolinyl)-guanidine hydrochloride), an agonist of acid-sensing ion channel type 3, has been increasingly used for in vivo studies of alternations in nociceptic behavior. In this study, we tried to investigate whether GMQ has any possible effect on other types of ion channels. Addition of GMQ to pituitary GH3 cells raised the amplitude of Ca²⁺-activated K⁺ currents (I_K(Ca)), which was reversed by verruculogen or PF1022A, but not by TRAM-39. Under inside-out current recordings, addition of GMQ into bath enhanced the probability of large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels with an EC₅₀ value of 0.95 µM. The activation curve of BK_Ca channels during exposure to GMQ shifted to a lower depolarized potential, with no change in the gating charge of the curve; however, there was a reduction of free energy for channel activation in its presence. As cells were exposed to GMQ, the amplitude of ion currents were suppressed, including delayed rectifying K⁺ current, voltage-gated Na⁺ and L-type Ca²⁺ currents. In Rolf B1.T olfactory sensory neuron, addition of GMQ was able to induce inward current and to suppress peak I_Na. Taken together, findings from these results indicated that in addition to the activation of ASIC3 channels, this compound might directly produce additional actions on various types of ion channels. Caution should be taken in the interpretation of in vivo experimental results when GMQ or other structurally similar compounds are used as targets to characterize the potential functions of ASIC3 channels.