Identification of Novel Cholesterol-binding Regions in Kir2 Channels

Rosenhouse‐Dantsker, Avia; Noskov, Sergei Y.; Durdağı, Serdar; Logothetis, Diomedes E.; Levitan, Irena

doi:10.1074/jbc.m113.496117

Cited by 97 publications

(132 citation statements)

References 66 publications

(87 reference statements)

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“…Increases in membrane cholesterol induced by exposure of cells to cholesterol-saturated methyl-β-cyclodextrin inhibits, while decreases in membrane cholesterol produced by methyl-β-cyclodextrin stimulates currents through K IR 2 channels in endothelial cells (382, 400, 1215, 1217, 1218) and in heterologously expressed K IR 2 channels (1214), with K IR 2.1 and 2.2 being particularly sensitive to cholesterol manipulation (1214). Two cholesterol-binding domains have been identified: one in the hinge region of M1 and a second at the interface between M1 and the cytosolic domains (1217). This cholesterol sensitivity involves several amino acids (L222, N216, and K219) in the CD loop of the carboxy terminus of K IR 2 channels that are also important for sensitivity to PIP 2 (382), and are part of a group of cytosolic residues that form a “cholesterol-sensitivity belt” around the putative pore of K IR 2 channels affecting gating of the channels (1216).…”

Section: Kir Channelsmentioning

confidence: 99%

“…This cholesterol sensitivity involves several amino acids (L222, N216, and K219) in the CD loop of the carboxy terminus of K IR 2 channels that are also important for sensitivity to PIP 2 (382), and are part of a group of cytosolic residues that form a “cholesterol-sensitivity belt” around the putative pore of K IR 2 channels affecting gating of the channels (1216). Studies of the bacterial K + channel K IR Bac1.1 and K IR 2.1 proteins incorporated into liposomes indicate that it is likely that cholesterol binds directly to the channel to modulate function (1308), through novel cholesterol binding motifs located near the hinge region of M1 and at the interface between M1 and the cytosolic domains (1217). …”

Section: Kir Channelsmentioning

confidence: 99%

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Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

259

347

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Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body’s tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes.

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Section: Kir Channelsmentioning

confidence: 99%

Section: Kir Channelsmentioning

confidence: 99%

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Tykocki

Boerman

Jackson

2017

Comprehensive Physiology

259

347

View full text Add to dashboard Cite

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“…; Rosenhouse‐Dantsker et al . ) and polyunsaturated fatty acids in the cardiac membrane that may exert anti‐arrhythmic activity by attenuating K v 7.1 channel function (Liin et al . ).…”

Section: Voltage‐gated K+ Channel Structure and Functionmentioning

confidence: 99%

Potassium channels in the heart: structure, function and regulation

Grandi

Sanguinetti

Bartos

et al. 2016

The Journal of Physiology

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This paper is the outcome of the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium, a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2016 symposium was 'K Channels and Regulation'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies and challenges on the topic of cardiac K channels. This paper summarizes the topics of formal presentations and informal discussions from the symposium on the structural basis of voltage-gated K channel function, as well as the mechanisms involved in regulation of K channel gating, expression and membrane localization. Given the critical role for K channels in determining the rate of cardiac repolarization, it is hardly surprising that essentially every aspect of K channel function is exquisitely regulated in cardiac myocytes. This regulation is complex and highly interrelated to other aspects of myocardial function. K channel regulatory mechanisms alter, and are altered by, physiological challenges, pathophysiological conditions, and pharmacological agents. An accompanying paper focuses on the integrative role of K channels in cardiac electrophysiology, i.e. how K currents shape the cardiac action potential, and how their dysfunction can lead to arrhythmias, and discusses K channel-based therapeutics. A fundamental understanding of K channel regulatory mechanisms and disease processes is fundamental to reveal new targets for human therapy.

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“…Membrane lipids in general can affect ion channel function by various means. Beyond the obvious physical changes that are caused by the alteration of the lipid composition, such as in fluidity and mechanical stress, it has become clear that lipids can also interact with ion channels in more specific ways, for example by rearranging the microdomain structure, modifying local electric potential profiles, or even specifically binding to them (Bock et al, 2003;Combs et al, 2013;Martens et al, 2000;Rosenhouse-Dantsker et al, 2013). VCF is well-suited for the study of such phenomena, as effects on the VSD or the pore can be distinguished.…”

Section: Slow Delayed Rectifier Potassium Channel Kv71mentioning

confidence: 99%

Molecular motions that shape the cardiac action potential: Insights from voltage clamp fluorometry

Zhu

Varga

Silva

2016

Progress in Biophysics and Molecular Biology

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Very recently, voltage-clamp fluorometry (VCF) protocols have been developed to observe the membrane proteins responsible for carrying the ventricular ionic currents that form the action potential (AP), including those carried by the cardiac Na þ channel, Na V 1.5, the L-type Ca 2þ channel, Ca V 1.2, the Na þ /K þ ATPase, and the rapid and slow components of the delayed rectifier, K V 11.1 and K V 7.1. This development is significant, because VCF enables simultaneous observation of ionic current kinetics with conformational changes occurring within specific channel domains. The ability gained from VCF, to connect nanoscale molecular movement to ion channel function has revealed how the voltage-sensing domains (VSDs) control ion flux through channel pores, mechanisms of post-translational regulation and the molecular pathology of inherited mutations. In the future, we expect that this data will be of great use for the creation of multi-scale computational AP models that explicitly represent ion channel conformations, connecting molecular, cell and tissue electrophysiology. Here, we review the VCF protocol, recent results, and discuss potential future developments, including potential use of these experimental findings to create novel computational models.

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Identification of Novel Cholesterol-binding Regions in Kir2 Channels

Cited by 97 publications

References 66 publications

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Potassium channels in the heart: structure, function and regulation

Molecular motions that shape the cardiac action potential: Insights from voltage clamp fluorometry

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