Abstract
Acid-sensing ionic channels (ASICs) have been shown to have a significant role in a growing number of physiological and pathological processes, such as nociception, synaptic transmission and plasticity, mechanosensation, and acidosis-induced neuronal injury. The discovery of pharmacological agents targeting ASICs has significant therapeutic potential and use as a research tool. In our work, we studied the action of transient perfusion (5–15 s) of aminoglycosides (AGs) (streptomycin and neomycin) on the proton-gated ionic currents in dorsal root ganglion (DRG) neurons of the rat and in human embryonic kidney (HEK)-293 cells. In DRG neurons, streptomycin and neomycin (30 μM) produced a significant, concentration-dependent, and reversible reduction in the amplitude of the proton-gated current, and a slowing of the desensitization rate of the ASIC current. Gentamycin (30 μM) also showed a significant reversible action on the ASIC currents. The curves of the pH effect for streptomycin and neomycin indicated that their effect was not significantly affected by pH. In HEK-293 cells, streptomycin (30 μM) produced a significant reduction in the amplitude of the proton-gated current. Neomycin and gentamycin had no significant action. Reduction of extracellular Ca2+ concentration produced a significant increase in the action of streptomycin and neomycin on the desensitization time course of ASIC currents. These results indicate that ASICs are molecular targets for AGs, which may contribute to the understanding of their actions on excitable cells. Moreover, AGs may constitute a source to develop novel molecules with a greater affinity, specificity, and selectivity for the different ASIC subunits.
Footnotes
This work was supported by the Consejo Nacional de Ciencia y Tecnología [Fellowship 193722 and 175945] (to A.G., O.L.R.); the Consejo Nacional de Ciencia y Tecnología [Grant 46511] (to E.S.); and the Vicerrectoria de Investigación y Estudios de Posgrado de la Benemérita Universidad Autónoma de Puebla [Grant SOEE-SAL-08-I] (to E.S.).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.152884
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- ANOVA
- analysis of variance
- ASICs
- acid-sensing ionic channels
- TRPV1
- transient receptor potential V1
- DRG
- dorsal root ganglion
- AG
- aminoglycoside
- ST
- streptomycin sulfate
- NEO
- neomycin sulfate
- GEN
- gentamycin sulfate
- hASIC1a
- human ASIC subunit 1a
- L15
- Leibovitz L15 medium
- TTX
- tetrodotoxin
- HEK
- human embryonic kidney
- nC
- nanoCoulombs
- A-317567
- (C-[6-[2-(1-isopropyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-cyclopropyl]-naphthalen-2-yl]-methanediamine).
- Received March 5, 2009.
- Accepted October 27, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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