NDLI: ATP sensitivity of ATP-sensitive K+ channels: role of the γ phosphate group of ATP and the R50 residue of mouse Kir6.2

Content Provider	PubMed Central
Author	John, Scott A. Weiss, James N. Bernard, Ribalet
Copyright Year	2005
Abstract	ATP-sensitive K (KATP) channels are composed of Kir6, the pore-forming protein, and the sulphonylurea receptor SUR, a regulatory protein. We and others have previously shown that positively charged residues in the C terminus of Kir6.2, including R201 and K185, interact with the α and β phosphate groups of ATP, respectively, to induce channel closure. A positively charged residue in the N terminus, R50, is also important, and has been proposed to interact with either the γ or β phosphate group of ATP. To examine this issue, we systematically mutated R50 to residues of different size, charge and hydropathy, and examined the effects on adenine nucleotide sensitivity in the absence and presence of SUR1. In the absence of SUR1, only the size of residue 50 significantly altered ATP sensitivity, with smaller side chains decreasing ATP sensitivity. In the presence of SUR1, however, hydrophathy and charge also played a role. Hydrophilic residues decreased ATP sensitivity more than hydrophobic residues for small size residues, and, surprisingly, negatively charged residues E and D preserved ATP sensitivity and increased ADP sensitivity relative to the wild-type residue R. These observations suggest that a negative charge near position 50, due to either mutation of R50 or the interaction of the γ phosphate group of ATP with R50, facilitates closure of the ATP-dependent gate. Mutation of the nearby positively charged residue R54, known to be involved in stabilizing channel opening via electrostatic interactions with phosphatidylinositol 4,5-bisphosphate (PIP2), also caused increased ADP sensitivity as compared with ATP, suggesting a loss of function of ATP's γ phosphate. Based on these results, we propose that a phosphate group or a negative charge at position 50 initiates channel closure by destabilizing the electrostatic interactions between negative phosphate groups of PIP2 and residues such as R54.
Related Links	http://dx.doi.org/10.1113/jphysiol.2005.095638
Starting Page	931
File Format	PDF
ISSN	14697793
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 3
Volume Number	568
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2005-11-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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