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Non‐proton ligand activation is linked to the ASIC3 calcium block site.
Author(s) -
Johnson Rachel N,
Gonzales Eric B
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.884.5
Subject(s) - acid sensing ion channel , biophysics , chemistry , extracellular , neurotransmission , calcium , ion channel , receptor , microbiology and biotechnology , biochemistry , biology , organic chemistry
Acid‐sensing ion channels (ASICs) are trimeric, sodium‐selective channels located throughout the central and peripheral nervous systems. ASICs are activated by extracellular protons and involved in ischemia, neurotransmission, and pain nociception. Currently, there is a lack of selective compounds that activate ASICs via nonproton mediated mechanisms. One compound, 2‐guanidine‐4‐ methylquinazoline (GMQ) selectively activates ASIC3. Controversy remains over the theoretical GMQ binding site in ASIC3. In order to determine this site, we have generated chimeric receptors combining the extracellular, transmembrane, and intracellular domains of rat ASIC3 and chicken ASIC1, and characterized them using whole‐cell path clamp electrophysiology. Our preliminary data confirm that ASIC3 is activated by a lowering of extracellular calcium concentration and enhanced by the addition of GMQ at pH 8.0, thus minimizing proton influence. However, both calcium and GMQ activation are absent in the chimeric ASIC receptors studied. Therefore, we hypothesize that GMQ acts via the ASIC3 calcium block site. Future studies will focus on elucidating the GMQ activation kinetics and key residues in both the extracellular and transmembrane domains critical for GMQ activity.