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Block of voltage‐dependent K + channels in insect muscle by the diacylhydrazine insecticide RH‐5849, 4‐aminopyridine, and quinidine
Author(s) -
Salgado Vincent L.
Publication year - 1992
Publication title -
archives of insect biochemistry and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.576
H-Index - 66
eISSN - 1520-6327
pISSN - 0739-4462
DOI - 10.1002/arch.940210307
Subject(s) - 4 aminopyridine , tetraethylammonium , quinidine , chemistry , biophysics , stereochemistry , biology , endocrinology , medicine , anatomy , pharmacology , potassium channel , potassium , organic chemistry
In calcium‐free saline, voltage‐clamped ventral longitudinal muscles of housefly larvae have maintained (I K ) and transient (I A ) voltage‐dependent K + currents. With 500 ms conditioning pulses, inactivation of I A had a midpoint at −53 mV and changed e‐fold in 3.46 mV. I A inactivated completely at −40 mV, with a time constant of 71 ms, allowing the effects of various K + channel blockers to be studied on I K in isolation. RH‐5849 (1,2‐dibenzoyl‐1‐ tert ‐butylhydrazine), a novel insect growth regulator, induces a lethal premature molt in insect larvae by mimicking the action of the molting hormone at ecdysone receptors. RH‐5849 also causes acute neurotoxicity in some insects by selectively blocking of I K in nerve and muscle. While most channel blockers have a Hill coefficient near 1, consistent with a simple one molecule per channel block mechanism, RH‐5849 and the analog RH‐1266 were found in the present study to block I K channels in insect muscle with a Hill coefficient of 1.5. The lC 50 (concentration that caused 50% block) for block of I K was 59 μM for RH‐5849 and 40 μM for RH‐1266. While tetraethylammonium blocked I K by only 20% at 100 mM, 4‐aminopyridine blocked the current with an lC 50 of 1.2 mM and a Hill coefficient of 0.97. Quinidine was the most potent blocker of I K in this study, with an lC 50 of 20 μM. Block of I K by either RH‐5849 or 4‐aminopyridine was independent of test pulse potential, but block by quinidine increased with depolarization. Block of I K by RH‐5849 and quinidine was time dependent, suggesting an open channel block mechanism, but the time course was too fast relative to channel activation for kinetic analysis. The lC 50 for block of I K by RH‐5849 decreased with temperature, with a Q 10 of 0.52. I A was also blocked by RH‐5849, but was less sensitive than I K . The lC 50 for block of I A by RH‐5849 was 775 μM, 13‐fold higher than the lC 50 for block of I K . © 1992 Wiley‐Liss, Inc.