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Molecular mechanism for sodium‐dependent activation of G protein‐gated K + channels
Author(s) -
Ho Ivan H. M.,
MurrellLagnado R. D.
Publication year - 1999
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.1999.00645.x
Subject(s) - g protein coupled inwardly rectifying potassium channel , chemistry , xenopus , phosphatidylinositol , biophysics , potassium channel , gating , sodium channel , g protein , membrane potential , microbiology and biotechnology , sodium , biochemistry , receptor , signal transduction , biology , organic chemistry , gene
1 G protein‐gated inwardly rectifying K + (GIRK) channels are activated independently by Gβγ and internal Na + via mechanisms requiring phosphatidylinositol phosphates. An aspartate (Asp) at position 226 in GIRK2 is crucial for Na + ‐dependent activation of GIRK1‐GIRK2 heteromeric channels. We expressed wild‐type and mutant GIRK1‐GIRK2 channels in Xenopus oocytes and tested the effects of Na + and neutralizing Asp226 on the functional interactions of the channels with phosphatidylinositol 4,5‐bisphosphate (PIP 2 ). 2 The rate of inhibition of GIRK1‐GIRK2 currents by application of anti‐PIP 2 antibody to inside‐out membrane patches was slowed > 2‐fold by the D226N mutation in GIRK2 and by increasing internal [Na + ]. The reverse mutation in GIRK1 (N217D) increased the rate of inhibition. 3 The dose‐response relationship for activation by purified PIP 2 was shifted to lower concentrations in the presence of 20 mM Na + . 4 Three synthetic isoforms of PIP 2 , PI(4,5)P 2 , PI(3,4)P 2 and PI(3,5)P 2 , activated GIRK channels with similar potencies. 5 We conclude that Na + directly interacts with Asp226 of GIRK2 to reduce the negative electrostatic potential and promote the functional interaction of the channels with PIP 2 .