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The Persistent Question of Potassium Channel Permeation Mechanisms.
Mironenko, A, Zachariae, U, de Groot, BL, Kopec, W
Journal of molecular biology. 2021;(17):167002
Abstract
Potassium channels play critical roles in many physiological processes, providing a selective permeation route for K+ ions in and out of a cell, by employing a carefully designed selectivity filter, evolutionarily conserved from viruses to mammals. The structure of the selectivity filter was determined at atomic resolution by x-ray crystallography, showing a tight coordination of desolvated K+ ions by the channel. However, the molecular mechanism of K+ ions permeation through potassium channels remains unclear, with structural, functional and computational studies often providing conflicting data and interpretations. In this review, we will present the proposed mechanisms, discuss their origins, and will critically assess them against all available data. General properties shared by all potassium channels are introduced first, followed by the introduction of two main mechanisms of ion permeation: soft and direct knock-on. Then, we will discuss critical computational and experimental studies that shaped the field. We will especially focus on molecular dynamics (MD) simulations, that provided mechanistic and energetic aspects of K+ permeation, but at the same time created long-standing controversies. Further challenges and possible solutions are presented as well.
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From Bench to Biomolecular Simulation: Phospholipid Modulation of Potassium Channels.
Pipatpolkai, T, Quetschlich, D, Stansfeld, PJ
Journal of molecular biology. 2021;(17):167105
Abstract
Potassium (K+) ion channels are crucial in numerous cellular processes as they hyperpolarise a cell through K+ conductance, returning a cell to its resting potential. K+ channel mutations result in multiple clinical complications such as arrhythmia, neonatal diabetes and migraines. Since 1995, the regulation of K+ channels by phospholipids has been heavily studied using a range of interdisciplinary methods such as cellular electrophysiology, structural biology and computational modelling. As a result, K+ channels are model proteins for the analysis of protein-lipid interactions. In this review, we will focus on the roles of lipids in the regulation of K+ channels, and how atomic-level structures, along with experimental techniques and molecular simulations, have helped guide our understanding of the importance of phospholipid interactions.
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Clinical Importance of the Human Umbilical Artery Potassium Channels.
Lorigo, M, Oliveira, N, Cairrao, E
Cells. 2020;(9)
Abstract
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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Beneficial Effects of High Potassium: Contribution of Renal Basolateral K+ Channels.
Staruschenko, A
Hypertension (Dallas, Tex. : 1979). 2018;(6):1015-1022
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Ca(2+) and ion channels in hypoxia-mediated pulmonary hypertension.
Lai, N, Lu, W, Wang, J
International journal of clinical and experimental pathology. 2015;(2):1081-92
Abstract
Alveolar hypoxia, a consequence of many lung diseases, can have adverse effects on the pulmonary vasculature. The changes that occur in the pulmonary circulation with exposure to chronic hypoxia include reductions in the diameter of the pulmonary arteries due to structural remodeling of the vasculature. Although the structural and functional changes that occur in the development of pulmonary hypertension have been well investigated, less is known about the cellular and molecular mechanisms of this process. This review will discuss the role of several potassium and calcium channels in hypoxic pulmonary vasoconstriction, both in elevating calcium influx into pulmonary artery smooth muscle cells (PASMCs). In addition to other signal transduction pathways, Ca(2+) signaling in PASMCs plays an important role in the development and progression of pulmonary hypertension due to its central roles in vasoconstriction and vascular remodeling. This review will focus on the effect of chronic hypoxia on ion channels and the potential pathogenic role of Ca(2+) signaling and regulation in the progression of pulmonary hypertension.
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Diversity of potassium channels in human umbilical artery smooth muscle cells: a review of their roles in human umbilical artery contraction.
Martín, P, Rebolledo, A, Palomo, AR, Moncada, M, Piccinini, L, Milesi, V
Reproductive sciences (Thousand Oaks, Calif.). 2014;(4):432-41
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Abstract
Through their control of cell membrane potential, potassium (K(+)) channels are among the best known regulators of vascular tone. This article discusses the expression and function of K(+) channels in human umbilical artery smooth muscle cells (HUASMCs). We review the bibliographic reports and also present single-channel data recorded in freshly isolated cells. Electrophysiological properties of big conductance, voltage- and Ca(2+)-sensitive K(+) channel and voltage-dependent K(+) channels are clearly established in this vessel, where they are involved in contractile state regulation. Their role in the maintenance of membrane potential is an important control mechanism in the determination of the vessel diameter. Additionally, small conductance Ca(2+)-sensitive K(+) channels, 2-pore domains K(+) channels and inward rectifier K(+) channels also appear to be present in HUASMCs, while intermediate conductance Ca(2+)-sensitive K(+) channels and ATP-sensitive K(+) channels could not be identified. In both cases, additional investigation is necessary to reach conclusive evidence of their expression and/or functional role in HUASMCs. Finally, we discuss the role of K(+) channels in pregnancy-related pathologies like gestational diabetes and preeclampsia.
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7.
Cl- and K+ channels and their role in primary brain tumour biology.
Turner, KL, Sontheimer, H
Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2014;(1638):20130095
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Profound cell volume changes occur in primary brain tumours as they proliferate, invade surrounding tissue or undergo apoptosis. These volume changes are regulated by the flux of Cl(-) and K(+) ions and concomitant movement of water across the membrane, making ion channels pivotal to tumour biology. We discuss which specific Cl(-) and K(+) channels are involved in defined aspects of glioma biology and how these channels are regulated. Cl(-) is accumulated to unusually high concentrations in gliomas by the activity of the NKCC1 transporter and serves as an osmolyte and energetic driving force for volume changes. Cell volume condensation is required as cells enter M phase of the cell cycle and this pre-mitotic condensation is caused by channel-mediated ion efflux. Similarly, Cl(-) and K(+) channels dynamically regulate volume in invading glioma cells allowing them to adjust to small extracellular brain spaces. Finally, cell condensation is a hallmark of apoptosis and requires the concerted activation of Cl(-) and Ca(2+)-activated K(+) channels. Given the frequency of mutation and high importance of ion channels in tumour biology, the opportunity exists to target them for treatment.
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Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning.
Busija, DW, Katakam, PV
Journal of vascular research. 2014;(3):175-89
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Mitochondrial-initiated events protect the neurovascular unit against lethal stress via a process called preconditioning, which independently promotes changes in cerebrovascular tone through shared signaling pathways. Activation of adenosine triphosphate (ATP)-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels) is a specific and dependable way to induce protection of neurons, astroglia, and cerebral vascular endothelium. Through the opening of mitoKATP channels, mitochondrial depolarization leads to activation of protein kinases and transient increases in cytosolic calcium (Ca(2+)) levels that activate terminal mechanisms that protect the neurovascular unit against lethal stress. The release of reactive oxygen species from mitochondria has similar protective effects. Signaling elements of the preconditioning pathways also are involved in the regulation of vascular tone. Activation of mitoKATP channels in cerebral arteries causes vasodilation, with cell-specific contributions from the endothelium, vascular smooth muscles, and nerves. Preexisting chronic conditions, such as insulin resistance and/or diabetes, prevent preconditioning and impair relaxation to mitochondrial-centered responses in cerebral arteries. Surprisingly, mitochondrial activation after anoxic or ischemic stress appears to protect cerebral vascular endothelium and promotes the restoration of blood flow; therefore, mitochondria may represent an important, but underutilized target in attenuating vascular dysfunction and brain injury in stroke patients.
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Lipid modulation of ion channels through specific binding sites.
Poveda, JA, Giudici, AM, Renart, ML, Molina, ML, Montoya, E, Fernández-Carvajal, A, Fernández-Ballester, G, Encinar, JA, González-Ros, JM
Biochimica et biophysica acta. 2014;(6):1560-7
Abstract
Ion channel conformational changes within the lipid membrane are a key requirement to control ion passage. Thus, it seems reasonable to assume that lipid composition should modulate ion channel function. There is increasing evidence that this implicates not just an indirect consequence of the lipid influence on the physical properties of the membrane, but also specific binding of selected lipids to certain protein domains. The result is that channel function and its consequences on excitability, contractility, intracellular signaling or any other process mediated by such channel proteins, could be subjected to modulation by membrane lipids. From this it follows that development, age, diet or diseases that alter lipid composition should also have an influence on those cellular properties. The wealth of data on the non-annular lipid binding sites in potassium channel from Streptomyces lividans (KcsA) makes this protein a good model to study the modulation of ion channel structure and function by lipids. The fact that this protein is able to assemble into clusters through the same non-annular sites, resulting in large changes in channel activity, makes these sites even more interesting as a potential target to develop lead compounds able to disrupt such interactions and hopefully, to modulate ion channel function. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.
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Protection of coronary endothelial function during cardiac surgery: potential of targeting endothelial ion channels in cardioprotection.
Yang, Q, Yu, CM, He, GW, Underwood, MJ
BioMed research international. 2014;:324364
Abstract
Vascular endothelium plays a critical role in the control of blood flow by producing vasoactive factors to regulate vascular tone. Ion channels, in particular, K(+) channels and Ca(2+)-permeable channels in endothelial cells, are essential to the production and function of endothelium-derived vasoactive factors. Impairment of coronary endothelial function occurs in open heart surgery that may result in reduction of coronary blood flow and thus in an inadequate myocardial perfusion. Hyperkalemic exposure and concurrent ischemia-reperfusion during cardioplegic intervention compromise NO and EDHF-mediated function and the impairment involves alterations of K(+) channels, that is, KATP and KCa, and Ca(2+)-permeable TRP channels in endothelial cells. Pharmacological modulation of these channels during ischemia-reperfusion and hyperkalemic exposure show promising results on the preservation of NO and EDHF-mediated endothelial function, which suggests the potential of targeting endothelial K(+) and TRP channels for myocardial protection during cardiac surgery.