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Extracellular chloride modulates the desensitization kinetics of acid‐sensing ion channel 1a (ASIC1a)
Author(s) -
KUSAMA NOBUYOSHI,
Benson Christopher J
Publication year - 2010
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.24.1_supplement.813.19
Subject(s) - acid sensing ion channel , chemistry , extracellular , biophysics , desensitization (medicine) , ion channel , patch clamp , hippocampal formation , biochemistry , biology , receptor , endocrinology
Acid‐sensing ion channels (ASICs) have Cl − ‐binding sites in the extracellular domain that are highly conserved between ASIC isoforms. In this experiment, we investigated the effect of Cl − ‐substitution on heterologously expressed ASIC1a current and ASIC current in hippocampal neurons by whole‐cell patch‐clamp method. Substitution of Cl − with the impermeable and inert anion, methansulfonate (MeS) did not alter the maximal current amplitude, pH sensitivity or steady‐state desensitization. However, the rate of desensitization was faster in MeS than in Cl − , and the tachyphylaxis of ASIC current was attenuated in MeS. Other anions (thiocyanate, Br − and I − ) also modified the kinetics of desensitization and tachyphylaxis. Next, we studied the effect of mutation of Cl − ‐binding sites. The pH sensitivity of mutants (K211A, R309A, E313A) was similar to that of wild type channel. However, these mutants showed a faster desensitization and an attenuated rundown. These mutations abolished the effect of anion substitution. Finally, we investigated the effect of Cl − substitution in hippocampal neuron. The modulation of the ASIC1a current in hippocampal neuron was similar to that in heterologously expressed ASIC1a. In addition to sensing pH changes, modulation of ASICs by anion fluxes associated with pathological conditions further positions the channels to sense changes in the extracellular environment.