Ho, Ivan H M and Murrell-Lagnado, R D (1999) Molecular determinants for sodium-dependent activation of G protein-gated K+ channels. Journal of Biological Chemistry, 274. pp. 8639-8648. ISSN 0021-9258

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Abstract

G protein-gated inwardly rectifying K+ channels (GIRKs) are activated by a direct interaction with Gbetagamma subunits and also by raised internal [Na+]. Both processes require the presence of phosphatidylinositol bisphosphate (PIP2). Here we show that the proximal C-terminal region of GIRK2 mediates the Na+-dependent activation of both the GIRK2 homomeric channels and the GIRK1/GIRK2 heteromeric channels. Within this region, GIRK2 has an aspartate at position 226, whereas GIRK1 has an asparagine at the equivalent position (217). A single point mutation, D226N, in GIRK2, abolished the Na+-dependent activation of both the homomeric and heteromeric channels. Neutralizing a nearby negative charge, E234S had no effect. The reverse mutation in GIRK1, N217D, was sufficient to restore Na+-dependent activation to the GIRK1N217D/GIRK2D226N heteromeric channels. The D226N mutation did not alter either the single channel properties or the ability of these channels to be activated via the m2-muscarinic receptor. PIP2 dramatically increased the open probability of GIRK1/GIRK2 channels in the absence of Na+ or Gbetagamma but did not preclude further activation by Na+, suggesting that Na+ is not acting simply to promote PIP2 binding to GIRKs. We conclude that aspartate 226 in GIRK2 plays a crucial role in Na+-dependent gating of GIRK1/GIRK2 channels.

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 11:31
Last Modified:	25 Mar 2015 11:31
URI:	http://srodev.sussex.ac.uk/id/eprint/52622

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