The dynamic interplay of PIP<sub>2</sub> and ATP in the regulation of the K<sub>ATP</sub> channel

Pipatpolkai, Tanadet; Usher, Samuel; Vedovato, Natascia; Ashcroft, Frances M.; Stansfeld, Phillip J.

doi:10.1113/jp283345

Cited by 10 publications

(9 citation statements)

References 71 publications

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“…The finding that some mutations reduce channel response to both ligands led to a hypothesis that these mutated residues may be involved in the binding of both ligands. Recently, molecular dynamics studies found that Kir6.2 residues R54 and K39 interact with both ATP and PIP 2 ( Pipatpolkai et al, 2022 ; Sung et al, 2022 ). Mutation of both R54 and K39 to alanine has been shown to reduce ATP as well as PIP 2 sensitivities ( Cukras et al, 2002 ).…”

Section: Structural Insights On K Atp Channel Regu...mentioning

confidence: 99%

Mechanistic insights on KATP channel regulation from cryo-EM structures

Driggers

Show-Ling

2022

Journal of General Physiology

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Gated by intracellular ATP and ADP, ATP-sensitive potassium (KATP) channels couple cell energetics with membrane excitability in many cell types, enabling them to control a wide range of physiological processes based on metabolic demands. The KATP channel is a complex of four potassium channel subunits from the Kir channel family, Kir6.1 or Kir6.2, and four sulfonylurea receptor subunits, SUR1, SUR2A, or SUR2B, from the ATP-binding cassette (ABC) transporter family. Dysfunction of KATP channels underlies several human diseases. The importance of these channels in human health and disease has made them attractive drug targets. How the channel subunits interact with one another and how the ligands interact with the channel to regulate channel activity have been long-standing questions in the field. In the past 5 yr, a steady stream of high-resolution KATP channel structures has been published using single-particle cryo-electron microscopy (cryo-EM). Here, we review the advances these structures bring to our understanding of channel regulation by physiological and pharmacological ligands.

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Section: Structural Insights On K Atp Channel Regu...mentioning

confidence: 99%

Mechanistic insights on KATP channel regulation from cryo-EM structures

Driggers

Show-Ling

2022

Journal of General Physiology

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“…(18) This combined with the recent in silico evidence suggesting PS may compete for the PIP2-binding site led us to investigate the PIP2-PS-Kir2.1 signaling axis in resistance arteries. There is also evidence indicating other vascular potassium channels, including SK and KATP, are regulated by PIP2 (61,62), and these channels may be affected in our vasodilation studies where exogenous lipids are added to intact arteries. However, our accumulation of evidence obtained from diverse experimental approaches gives us confidence in concluding that PS inhibits Kir2.1-mediated vasodilation through an interaction at the MEJ.…”

Section: Phosphatidylserine Regulation Of Kir21mentioning

confidence: 77%

Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1

Ruddiman¹,

Peckham²,

Luse³

et al. 2023

JCI Insight

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Lipid regulation of ion channels is largely explored using in silico modeling with minimal experimentation in intact tissue; thus, the functional consequences of these predicted lipid-channel interactions within native cellular environments remain elusive. The goal of this study is to investigate how lipid regulation of endothelial Kir2.1, an inwardly rectifying potassium channel that regulates membrane hyperpolarization, contributes to vasodilation in resistance arteries. First, we show phosphatidylserine (PS) localizes to a specific subpopulation of myoendothelial junctions (MEJs), crucial signaling microdomains that regulate vasodilation in resistance arteries, and in silico data has implied PS may compete with PIP2 binding on Kir2.1. We found 83.33% of Kir2.1-MEJs also contained PS, possibly indicating an interaction where PS regulates Kir2.1. Electrophysiology experiments on HEK cells demonstrate PS blocks PIP2 activation ofKir2.1, and addition of exogenous PS blocks PIP2-mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries (Eln fl/fl /Cdh5-Cre), PS localization in endothelium was disrupted and PIP2 activation of Kir2.1 was significantly increased. Taken together, our data suggests PS enrichment to MEJs inhibits PIP2-mediated activation of Kir2.1 to tightly regulate changes in arterial diameter, and demonstrates the intracellular lipid localization within endothelium is an important determinant of vascular function.

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“…2b, 5c). Previous molecular dynamics simulations, using ATP-bound closed structures of Kir6.2 tetramer 51 or tetramer of Kir6.2 plus SUR1-TMD0 38 with a single PIP 2 molecule docked in the conserved PIP 2 binding site, found that Kir6.2-K39 51 or both K39 and R54 38 switched between ATP binding and PIP 2 binding. In the SUR1/Kir6.2 Q52R open structure, we see Kir6.2-K39, rather than binding PIP 2 in the conserved site, binds the second PIP 2 in the novel site.…”

Section: Discussionmentioning

confidence: 99%

Structure of an open K_ATPchannel reveals tandem PIP₂binding sites mediating the Kir6.2 and SUR1 regulatory interface

Driggers

Kuo

Zhu

et al. 2023

Preprint

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ATP-sensitive potassium (KATP) channels, composed of four pore-lining Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic β-cells. KATPchannel opening is stimulated by PIP2and inhibited by ATP. Mutations that increase channel opening by PIP2reduce ATP inhibition and cause neonatal diabetes. Although considerable evidence has indicated PIP2in KATPchannel function, previously solved open-channel structures have lacked bound PIP2, and mechanisms by which PIP2regulates KATPchannels remain unresolved. Here, we report cryoEM structure of a KATPchannel harboring the neonatal diabetes mutation Kir6.2-Q52R, bound to PIP2in open conformation. The structure reveals two adjacent PIP2molecules between SUR1 and Kir6.2. The first PIP2binding site is conserved among PIP2-gated Kir channels. The second site forms uniquely in KATPat the interface of Kir6.2 and SUR1. Functional studies demonstrate both binding sites determine channel activity. Kir6.2 pore opening is associated with a twist of the Kir6.2 cytoplasmic domain and a rotation of the N-terminal transmembrane domain of SUR1, which widens the inhibitory ATP binding pocket to disfavor ATP binding. The open conformation is particularly stabilized by the Kir6.2-Q52R residue through cation-π bonding with SUR1-W51. Together, these results uncover the cooperation between SUR1 and Kir6.2 in PIP2binding and gating, explain the antagonistic regulation of KATPchannels by PIP2and ATP, and provide the mechanism by which Kir6.2-Q52R stabilizes an open channel to cause neonatal diabetes.

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The dynamic interplay of PIP₂ and ATP in the regulation of the K_ATP channel

Cited by 10 publications

References 71 publications

Mechanistic insights on KATP channel regulation from cryo-EM structures

Mechanistic insights on KATP channel regulation from cryo-EM structures

Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1

Structure of an open K_ATPchannel reveals tandem PIP₂binding sites mediating the Kir6.2 and SUR1 regulatory interface

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The dynamic interplay of PIP2 and ATP in the regulation of the KATP channel

Cited by 10 publications

References 71 publications

Mechanistic insights on KATP channel regulation from cryo-EM structures

Mechanistic insights on KATP channel regulation from cryo-EM structures

Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1

Structure of an open KATPchannel reveals tandem PIP2binding sites mediating the Kir6.2 and SUR1 regulatory interface

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The dynamic interplay of PIP₂ and ATP in the regulation of the K_ATP channel

Structure of an open K_ATPchannel reveals tandem PIP₂binding sites mediating the Kir6.2 and SUR1 regulatory interface