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The dynamic interplay of PIP 2 and ATP in the regulation of the K ATP channel
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Pipatpolkai, Tanadet, Usher, Samuel G., Vedovato, Natascia, Ashcroft, Frances M. and Stansfeld, Phillip J. (2022) The dynamic interplay of PIP 2 and ATP in the regulation of the K ATP channel. The Journal of Physiology, 600 (20). pp. 4503-4519. doi:10.1113/JP283345 ISSN 0022-3751.
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Official URL: http://dx.doi.org/10.1113/JP283345
Abstract
ATP-sensitive potassium (KATP) channels couple the intracellular ATP concentration to insulin secretion. KATP channel activity is inhibited by ATP binding to the Kir6.2 tetramer and activated by phosphatidylinositol-4,5-bisphosphate (PIP2). Here, we use molecular dynamics (MD) simulation, electrophysiology and fluorescence spectroscopy to show that ATP and PIP2 occupy different binding pockets that share a single amino acid residue, K39. When both ligands are present, simulations suggest that K39 shows a greater preference to co-ordinate with PIP2 than ATP. They also predict that a neonatal diabetes mutation at K39 (K39R) increases the number of hydrogen bonds formed between K39 and PIP2, potentially accounting for the reduced ATP inhibition observed in electrophysiological experiments. Our work suggests PIP2 and ATP interact allosterically to regulate KATP channel activity.
Item Type: | Journal Article | ||||||||||||||||||
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Subjects: | Q Science > QH Natural history Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||||||||
Library of Congress Subject Headings (LCSH): | Potassium channels, Molecular dynamics, Phosphoinositides, Ion channels -- Metabolism | ||||||||||||||||||
Journal or Publication Title: | The Journal of Physiology | ||||||||||||||||||
Publisher: | Wiley | ||||||||||||||||||
ISSN: | 0022-3751 | ||||||||||||||||||
Official Date: | 15 October 2022 | ||||||||||||||||||
Dates: |
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Volume: | 600 | ||||||||||||||||||
Number: | 20 | ||||||||||||||||||
Page Range: | pp. 4503-4519 | ||||||||||||||||||
DOI: | 10.1113/JP283345 | ||||||||||||||||||
Status: | Peer Reviewed | ||||||||||||||||||
Publication Status: | Published | ||||||||||||||||||
Reuse Statement (publisher, data, author rights): | This is the peer reviewed version of the following article: Pipatpolkai, T., Usher, S.G., Vedovato, N., Ashcroft, F.M. and Stansfeld, P.J. (2022), The dynamic interplay of PIP2 and ATP in the regulation of the KATP channel. J Physiol. Accepted Author Manuscript. https://doi.org/10.1113/JP283345 which has been published in final form at http://dx.doi.org/10.1113/JP283345. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited | ||||||||||||||||||
Access rights to Published version: | Restricted or Subscription Access | ||||||||||||||||||
Date of first compliant deposit: | 7 September 2022 | ||||||||||||||||||
Date of first compliant Open Access: | 1 September 2023 | ||||||||||||||||||
RIOXX Funder/Project Grant: |
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