Molecular mechanism for sodium-dependent activation of G protein-gated K+ channels

Ho, Ivan H M and Murrell-Lagnado, R D (1999) Molecular mechanism for sodium-dependent activation of G protein-gated K+ channels. Journal of Physiology, 520 (3). pp. 645-651. ISSN 0022-3751

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1. G protein-gated inwardly rectifying K+ (GIRK) channels are activated independently by Gbetagamma 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 (PIP2). 2. The rate of inhibition of GIRK1-GIRK2 currents by application of anti-PIP2 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 PIP2 was shifted to lower concentrations in the presence of 20 mM Na+. 4. Three synthetic isoforms of PIP2, PI(4,5)P2, PI(3,4)P2 and PI(3,5)P2, 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 PIP2.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QH Natural history > QH0301 Biology
Depositing User: Tom Gittoes
Date Deposited: 25 Mar 2015 11:19
Last Modified: 25 Mar 2015 11:19
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