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

2005; American Society for Pharmacology and Experimental Therapeutics; Volume: 314; Issue: 3 Linguagem: Inglês

10.1124/jpet.105.085928

1521-0103

Refik Kanjhan, Elizabeth J. Coulson, David J. Adams, Mark C. Bellingham,

Ion channel regulation and function

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 Ca 2+ -activated large conductance K + channel (BK or MaxiK; α-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 (Ca 2+ , Mg 2+ , Zn 2+ , and Ba 2+ ) 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 Ca 2+ -activated K + channels by tertiapin-Q at nanomolar range via different mechanisms may have implications in pain physiology and therapy.