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Challenges and advances in atomistic simulations of potassium and sodium ion channel gating and permeation.
DeMarco, KR, Bekker, S, Vorobyov, I
The Journal of physiology. 2019;(3):679-698
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Abstract
Ion channels are implicated in many essential physiological events such as electrical signal propagation and cellular communication. The advent of K+ and Na+ ion channel structure determination has facilitated numerous investigations of molecular determinants of their behaviour. At the same time, rapid development of computer hardware and molecular simulation methodologies has made computational studies of large biological molecules in all-atom representation tractable. The concurrent evolution of experimental structural biology with biomolecular computer modelling has yielded mechanistic details of fundamental processes unavailable through experiments alone, such as ion conduction and ion channel gating. This review is a short survey of the atomistic computational investigations of K+ and Na+ ion channels, focusing on KcsA and several voltage-gated channels from the KV and NaV families, which have garnered many successes and engendered several long-standing controversies regarding the nature of their structure-function relationship. We review the latest advancements and challenges facing the field of molecular modelling and simulation regarding the structural and energetic determinants of ion channel function and their agreement with experimental observations.
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Implications of Dynamic Occupancy, Binding Kinetics, and Channel Gating Kinetics for hERG Blocker Safety Assessment and Mitigation.
Pearlstein, RA, MacCannell, KA, Erdemli, G, Yeola, S, Helmlinger, G, Hu, QY, Farid, R, Egan, W, Whitebread, S, Springer, C, et al
Current topics in medicinal chemistry. 2016;(16):1792-818
Abstract
Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP. Gating effects differ for compounds that are sterically compatible with closed channels (becoming trapped in deactivated channels) versus those that are incompatible with the closed/closing state, and expelled during deactivation. Occupancies of trappable blockers build to equilibrium levels, whereas those of non-trappable blockers build and decay during each AP cycle. Occupancies of ~83% (non-trappable) versus ~63% (trappable) of open/inactive channels caused EADs in our AP simulations. Overall, we conclude that hERG occupancy at therapeutic exposure levels may be tolerated for nontrappable, but not trappable blockers capable of building to the proarrhythmic occupancy level. Furthermore, the widely used Redfern safety index may be biased toward trappable blockers, overestimating the exposure-IC50 separation in nontrappable cases.
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Connexin 43 and CaV1.2 Ion Channel Trafficking in Healthy and Diseased Myocardium.
Basheer, WA, Shaw, RM
Circulation. Arrhythmia and electrophysiology. 2016;(6):e001357
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Structure of potassium channels.
Kuang, Q, Purhonen, P, Hebert, H
Cellular and molecular life sciences : CMLS. 2015;(19):3677-93
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Abstract
Potassium channels ubiquitously exist in nearly all kingdoms of life and perform diverse but important functions. Since the first atomic structure of a prokaryotic potassium channel (KcsA, a channel from Streptomyces lividans) was determined, tremendous progress has been made in understanding the mechanism of potassium channels and channels conducting other ions. In this review, we discuss the structure of various kinds of potassium channels, including the potassium channel with the pore-forming domain only (KcsA), voltage-gated, inwardly rectifying, tandem pore domain, and ligand-gated ones. The general properties shared by all potassium channels are introduced first, followed by specific features in each class. Our purpose is to help readers to grasp the basic concepts, to be familiar with the property of the different domains, and to understand the structure and function of the potassium channels better.
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RGK regulation of voltage-gated calcium channels.
Buraei, Z, Lumen, E, Kaur, S, Yang, J
Science China. Life sciences. 2015;(1):28-38
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Abstract
Voltage-gated calcium channels (VGCCs) play critical roles in cardiac and skeletal muscle contractions, hormone and neurotransmitter release, as well as slower processes such as cell proliferation, differentiation, migration and death. Mutations in VGCCs lead to numerous cardiac, muscle and neurological disease, and their physiological function is tightly regulated by kinases, phosphatases, G-proteins, calmodulin and many other proteins. Fifteen years ago, RGK proteins were discovered as the most potent endogenous regulators of VGCCs. They are a family of monomeric GTPases (Rad, Rem, Rem2, and Gem/Kir), in the superfamily of Ras GTPases, and they have two known functions: regulation of cytoskeletal dynamics including dendritic arborization and inhibition of VGCCs. Here we review the mechanisms and molecular determinants of RGK-mediated VGCC inhibition, the physiological impact of this inhibition, and recent evidence linking the two known RGK functions.
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Determinants of cation transport selectivity: Equilibrium binding and transport kinetics.
Lockless, SW
The Journal of general physiology. 2015;(1):3-13
Abstract
The crystal structures of channels and transporters reveal the chemical nature of ion-binding sites and, thereby, constrain mechanistic models for their transport processes. However, these structures, in and of themselves, do not reveal equilibrium selectivity or transport preferences, which can be discerned only from various functional assays. In this Review, I explore the relationship between cation transport protein structures, equilibrium binding measurements, and ion transport selectivity. The primary focus is on K(+)-selective channels and nonselective cation channels because they have been extensively studied both functionally and structurally, but the principles discussed are relevant to other transport proteins and molecules.
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The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels.
Dascal, N, Kahanovitch, U
International review of neurobiology. 2015;:27-85
Abstract
G protein-gated K(+) (GIRK, or Kir3) channels mediate inhibitory neurotransmission via G protein-coupled receptors (GPCRs) in heart and brain. The signaling cascade involves activation of GPCR by an agonist, activation of a G protein followed by rearrangement or dissociation of activated Gα(GTP) from Gβγ, and activation of GIRK by Gβγ. Gβγ is the main transducer of GPCR activating signal to the GIRK channel. It promotes channel opening by direct binding to GIRK's cytosolic domain formed by the N- and C-terminal segments of the GIRK's four subunits. Gβγ's interaction with, and activation of, the GIRK channels are well understood and reviewed elsewhere; however, several important details involving distal parts of the cytosolic domain remain incompletely understood. Gα(i/o) also binds to GIRKs and has been implicated in regulating channel's gating, in concert with Gβγ. Among known functions of Gα, best-described (though not well understood) are selectivity of signaling (only G(i/o) proteins normally couple to GIRKs) and regulation of the basal activity of GIRKs (I(basal)). A role for a direct effect of the activated Gα(i/o)(GTP) in GIRK gating has also been proposed but remains elusive. This chapter discusses the mechanisms of signaling within the essential cascade, from GPCR to the heterotrimeric G protein and to the channel. The focus is on the role of Gα and on the relationships between Gα and Gβγ in channel regulation, their role in specific signaling from GPCRs to GIRKs, and the role of stoichiometry and cooperativity of G protein-GIRK interactions in channel's function.
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Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death.
Wagner, S, Maier, LS, Bers, DM
Circulation research. 2015;(12):1956-70
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Abstract
Despite improvements in the therapy of underlying heart disease, sudden cardiac death is a major cause of death worldwide. Disturbed Na and Ca handling is known to be a major predisposing factor for life-threatening tachyarrhythmias. In cardiomyocytes, many ion channels and transporters, including voltage-gated Na and Ca channels, cardiac ryanodine receptors, Na/Ca-exchanger, and SR Ca-ATPase are involved in this regulation. We have learned a lot about the pathophysiological relevance of disturbed ion channel function from monogenetic disorders. Changes in the gating of a single ion channel and the activity of an ion pump suffice to dramatically increase the propensity for arrhythmias even in structurally normal hearts. Nevertheless, patients with heart failure with acquired dysfunction in many ion channels and transporters exhibit profound dysregulation of Na and Ca handling and Ca/calmodulin-dependent protein kinase and are especially prone to arrhythmias. A deeper understanding of the underlying arrhythmic principles is mandatory if we are to improve their outcome. This review addresses basic tachyarrhythmic mechanisms, the underlying ionic mechanisms and the consequences for ion homeostasis, and the situation in complex diseases like heart failure.
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Structure and gating of CLC channels and exchangers.
Accardi, A
The Journal of physiology. 2015;(18):4129-38
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Abstract
Since their serendipitous discovery the CLC family of Cl(-) transporting proteins has been a never ending source of surprises. From their double-barrelled architecture to their complex structure and divergence as channels and transporters, the CLCs never cease to amaze biophysicists, biochemists and physiologists alike. These unusual functional properties allow the CLCs to fill diverse physiological niches, regulating processes that range from muscle contraction to acidification of intracellular organelles, nutrient accumulation and survival of bacteria to environmental stresses. Over the last 15 years, the availability of atomic-level information on the structure of the CLCs, coupled to the discovery that the family is divided into passive channels and secondary active transporters, has revolutionized our understanding of their function. These breakthroughs led to the identification of the key structural elements regulating gating, transport, selectivity and regulation by ligands. Unexpectedly, many lines of evidence indicate that the CLC exchangers function according to a non-conventional transport mechanism that defies the fundamental tenets of the alternating-access paradigm for exchange transport, paving the way for future unexpected insights into the principles underlying active transport and channel gating.
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What can naturally occurring mutations tell us about Ca(v)1.x channel function?
Stockner, T, Koschak, A
Biochimica et biophysica acta. 2013;(7):1598-607
Abstract
Voltage-gated Ca²⁺ channels allow for Ca²⁺-dependent intracellular signaling by directly mediating Ca²⁺ ion influx, by physical coupling to intracellular Ca²⁺ release channels or functional coupling to other ion channels such as Ca²⁺ activated potassium channels. L-type Ca²⁺ channels that comprise the family of Ca(v)1 channels are expressed in many electrically excitable tissues and are characterized by their unique sensitivity to dihydropyridines. In this issue, we summarize genetic defects in L-type Ca²⁺ channels and analyze their role in human diseases (Ca²⁺ channelopathies); e.g. mutations in Ca(v)1.2 α1 cause Timothy and Brugada syndrome, mutations in Ca(v)1.3 α1 are linked to sinoatrial node dysfunction and deafness while mutations in Ca(v)1.4 α1 are associated with X-linked retinal disorders such as an incomplete form of congenital stationary night blindness. Herein, we also put the mutations underlying the channel's dysfunction into the structural context of the pore-forming α1 subunit. This analysis highlights the importance of combining functional data with structural analysis to gain a deeper understanding for the disease pathophysiology as well as for physiological channel function. This article is part of a Special Issue entitled: Calcium channels.