JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Issue Date:
2000
Abstract(summary):
Tertiapin is a 21-residue peptide isolated from honey bee venoms. A recent study indicated that tertiapin is a potent blocker of certain types of inwardly rectifying K+ (Kir) channels (Jin and Lu, 1998). We examined the effect of tertiapin on ion channel currents in rabbit cardiac myocytes using the patch-clamp technique. In the whole-cell configuration, tertiapin fully inhibited acetylcholine(1 mu M)-induced muscarinic K+ (K-ACh) channel currents in atrial myocytes with the half-maximum inhibitory concentration of similar to 8 nM through similar to 1:1 stoichiometry. The potency of tertiapin in inhibiting K-ACh channels was not significantly different at -40 and -100 mV. Tertiapin also inhibited the K-ACh channel preactivated by intracellular guanosine 5'-O-(3-thiotriphosphate), a nonhydrolyzable GTP analog. A constitutively active Kir channel, the I-K1 channel, was at least 100 times less sensitive to tertiapin. Another Kir channel in cardiac myocytes, the ATP-sensitive K+ channel, was virtually insensitive to tertiapin (1 mu M). The voltage-dependent K+ and the L-type Ca2+ channels were not affected by tertiapin (1 1 mu M) At the single-channel level, tertiapin inhibited the K-ACh channel from the outside of the membrane by reducing the NPo (N is the number of functional channels, and the P-o is the open probability of each channel) without affecting the single-channel conductance or fast kinetics. Therefore, tertiapin potently and selectively blocks the K-ACh, channel in cardiac myocytes in a receptor- and voltage-independent manner. Tertiapin is a novel pharmacological tool to identify the functional role of the K-ACh channel in the parasympathetic regulation of the heart beat.