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Subunit dependent modulation of ASIC currents by intracellular pH
Author(s) -
Li Minghua,
Ingram Susan L,
Simon Roger P,
Xiong Zhigang
Publication year - 2012
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.26.1_supplement.1048.11
Subject(s) - acid sensing ion channel , intracellular , chemistry , extracellular , intracellular ph , biophysics , protein subunit , microbiology and biotechnology , mutant , amino acid , biochemistry , ion channel , biology , receptor , gene
Activation of acid‐sensing ion channels (ASICs) plays an important role in acidosis‐mediated, glutamate receptor‐independent ischemic brain injury. Although ASICs are activated by a decrease in extracellular pH, our recent studies have demonstrated that neuronal ASICs are closely regulated by changes of intracellular pH (pHi). Since ASICs in native neurons are composed of different subunits with distinct electrophysiological/pharmacological properties, we determined whether the modulation of the ASIC activity by pHi is subunit dependent and determined potential sites on the ASIC channel involved in the modulation by pHi. We show that the potentiation of ASICs by pHi alkalizing agent quinine depends on the presence of the ASIC1a or 2a subunits. Similar to its effect on the ASICs in native neurons, increasing intracellular pH shifted the activation curves of the ASIC1a and 2a channels to less acidic pH values while the steady state inactivation curve was shifted to more acid pH values. To identify the amino acids involved in the modulation of ASICs by pHi, the effects of quinine on point mutation mutants were determined. Quinine still potentiates ASIC currents in ASIC1a K4R, S17A, Q19A, Y36A and L39A mutants. Quinine also potentiates ASIC currents from ASIC1b (N‐1‐42aa)/1a(43aa‐C‐terminus) chimeras. However, quinine failed to potentiate the current from an ASIC1b(N‐1‐52aa)/1a(54aa‐C‐terminus) chimera.