A constricted opening in Kir channels does not impede potassium conduction

Black, Katrina A.; He, Sitong; Jin, Ruitao; Miller, David M.; Bolla, Jani Reddy; Clarke, Oliver; Johnson, Paul; Windley, Monique J.; Burns, Christopher J.; Hill, Adam P.; Laver, Derek R.; Robinson, Carol V.; Smith, Brian J.; Gulbis, Jacqueline M.

doi:10.1038/s41467-020-16842-0

Cited by 17 publications

(24 citation statements)

References 72 publications

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“…The pore diameter at the inner helix (F192) and G-loop (M313) gates is ~6.5 Å and 4 Å, respectively, which is too small for hydrated K + (~8 Å) to permeate ( Figure 3B ). However, previous studies utilizing cross-linked KirBac3.1 channels ( Black et al, 2020 ) and MD simulations of GIRK channels ( Bernsteiner et al, 2019 ) suggest this extent of opening at the inner-helix gate may be sufficient to pass partially hydrated or transiently non-hydrated K + .…”

Section: Resultsmentioning

confidence: 94%

Structural insights into GIRK2 channel modulation by cholesterol and PIP2

et al. 2021

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SUMMARY G-protein-gated inwardly rectifying potassium (GIRK) channels are important for determining neuronal excitability. In addition to G proteins, GIRK channels are potentiated by membrane cholesterol, which is elevated in the brains of people with neurodegenerative diseases such as Alzheimer’s dementia and Parkinson’s disease. The structural mechanism of cholesterol modulation of GIRK channels is not well understood. In this study, we present cryo-electron microscopy (cryoEM) structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS) and phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The structures reveal that CHS binds near PIP 2 in lipid-facing hydrophobic pockets of the transmembrane domain. Our structural analysis suggests that CHS stabilizes PIP 2 interaction with the channel and promotes engagement of the cytoplasmic domain onto the transmembrane region. Mutagenesis of one of the CHS binding pockets eliminates cholesterol-dependent potentiation of GIRK2. Elucidating the structural mechanisms underlying cholesterol modulation of GIRK2 channels could facilitate the development of therapeutics for treating neurological diseases.

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Section: Resultsmentioning

confidence: 94%

Structural insights into GIRK2 channel modulation by cholesterol and PIP2

et al. 2021

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“…Overall, none of the structures showed pore radii large enough to enable hydrated K + flux through a continuous pore. Even though recent studies suggest that partially dehydrated K + ions can pass the HBC gate formed by aromatic side chains ( Bernsteiner et al, 2019 ; Black et al, 2020 ), the constrictions at sites 1 and 3 are formed by hydrophobic residues, rendering K + passage (especially at site 1) very unlikely.…”

Section: Resultsmentioning

confidence: 99%

Simulating PIP2-Induced Gating Transitions in Kir6.2 Channels

Bründl

Pellikan

Stary-Weinzinger

2021

Front. Mol. Biosci.

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ATP-sensitive potassium (KATP) channels consist of an inwardly rectifying K+ channel (Kir6.2) pore, to which four ATP-sensitive sulfonylurea receptor (SUR) domains are attached, thereby coupling K+ permeation directly to the metabolic state of the cell. Dysfunction is linked to neonatal diabetes and other diseases. K+ flux through these channels is controlled by conformational changes in the helix bundle region, which acts as a physical barrier for K+ permeation. In addition, the G-loop, located in the cytoplasmic domain, and the selectivity filter might contribute to gating, as suggested by different disease-causing mutations. Gating of Kir channels is regulated by different ligands, like Gβγ, H+, Na+, adenosine nucleotides, and the signaling lipid phosphatidyl-inositol 4,5-bisphosphate (PIP2), which is an essential activator for all eukaryotic Kir family members. Although molecular determinants of PIP2 activation of KATP channels have been investigated in functional studies, structural information of the binding site is still lacking as PIP2 could not be resolved in Kir6.2 cryo-EM structures. In this study, we used Molecular Dynamics (MD) simulations to examine the dynamics of residues associated with gating in Kir6.2. By combining this structural information with functional data, we investigated the mechanism underlying Kir6.2 channel regulation by PIP2.

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“…[ 77 , 78 ]. TM1 (the outer helix) makes contact with TM2 (the inner helix), which lines the pore of the channel and forms an “inverted tepee” in a closed channel conformation [ 1 , 75 , 79 ]. These channels are encoded by members of the Kir gene family.…”

Section: Diversity Of K + Channels In Huamentioning

confidence: 99%

Clinical Importance of the Human Umbilical Artery Potassium Channels

Lorigo

Oliveira

2020

Cells

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Potassium (K+) channels are usually predominant in the membranes of vascular smooth muscle cells (SMCs). These channels play an important role in regulating the membrane potential and vessel contractility—a role that depends on the vascular bed. Thus, the activity of K+ channels represents one of the main mechanisms regulating the vascular tone in physiological and pathophysiological conditions. Briefly, the activation of K+ channels in SMC leads to hyperpolarization and vasorelaxation, while its inhibition induces depolarization and consequent vascular contraction. Currently, there are four different types of K+ channels described in SMCs: voltage-dependent K+ (KV) channels, calcium-activated K+ (KCa) channels, inward rectifier K+ (Kir) channels, and 2-pore domain K+ (K2P) channels. Due to the fundamental role of K+ channels in excitable cells, these channels are promising therapeutic targets in clinical practice. Therefore, this review discusses the basic properties of the various types of K+ channels, including structure, cellular mechanisms that regulate their activity, and new advances in the development of activators and blockers of these channels. The vascular functions of these channels will be discussed with a focus on vascular SMCs of the human umbilical artery. Then, the clinical importance of K+ channels in the treatment and prevention of cardiovascular diseases during pregnancy, such as gestational hypertension and preeclampsia, will be explored.

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A constricted opening in Kir channels does not impede potassium conduction

Cited by 17 publications

References 72 publications

Structural insights into GIRK2 channel modulation by cholesterol and PIP2

Structural insights into GIRK2 channel modulation by cholesterol and PIP2

Simulating PIP2-Induced Gating Transitions in Kir6.2 Channels

Clinical Importance of the Human Umbilical Artery Potassium Channels

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