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NEUROPHARMACOLOGY

Tertiapin-Q Blocks Recombinant and Native Large Conductance K⁺ Channels in a Use-Dependent Manner

School of Biomedical Sciences (R.K., E.J.C., D.J.A., M.C.B.) and The Queensland Brain Institute (E.J.C.), University of Queensland, Brisbane, Australia

Tertiapin, a short peptide from honey bee venom, has been reported to specifically block the inwardly rectifying K⁺ (Kir) channels, including G protein-coupled inwardly rectifying potassium channel (GIRK) 1+GIRK4 heteromultimers and ROMK1 homomultimers. In the present study, the effects of a stable and functionally similar derivative of tertiapin, tertiapin-Q, were examined on recombinant human voltage-dependent Ca²⁺-activated large conductance K⁺ channel (BK or MaxiK; -subunit or hSlo1 homomultimers) and mouse inwardly rectifying GIRK1+GIRK2 (i.e., Kir3.1 and Kir3.2) heteromultimeric K⁺ channels expressed in Xenopus oocytes and in cultured newborn mouse dorsal root ganglion (DRG) neurons. In two-electrode voltage-clamped oocytes, tertiapin-Q (1-100 nM) inhibited BK-type K⁺ channels in a use- and concentration-dependent manner. We also confirmed the inhibition of recombinant GIRK1+GIRK2 heteromultimers by tertiapin-Q, which had no effect on endogenous depolarization- and hyperpolarization-activated currents sensitive to extracellular divalent cations (Ca²⁺, Mg²⁺, Zn²⁺, and Ba²⁺) in defolliculated oocytes. In voltage-clamped DRG neurons, tertiapin-Q voltage- and use-dependently inhibited outwardly rectifying K⁺ currents, but Cs⁺-blocked hyperpolarization-activated inward currents including I_H were insensitive to tertiapin-Q, baclofen, barium, and zinc, suggesting absence of functional GIRK channels in the newborn. Under current-clamp conditions, tertiapin-Q blocked the action potential after hyperpolarization (AHP) and increased action potential duration in DRG neurons. Taken together, these results demonstrate that the blocking actions of tertiapin-Q are not specific to Kir channels and that the blockade of recombinant BK channels and native neuronal AHP currents is use-dependent. Inhibition of specific types of Kir and voltage-dependent Ca²⁺-activated K⁺ channels by tertiapin-Q at nanomolar range via different mechanisms may have implications in pain physiology and therapy.

Address correspondence to: Dr. Refik Kanjhan, School of Biomedical Sciences, University of Queensland, St. Lucia 4072 Queensland, Australia. E-mail: r.kanjhan{at}uq.edu.au

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