scholarly journals Atomistic Insights of Calmodulin Gating of Complete Ion Channels

2020 ◽  
Vol 21 (4) ◽  
pp. 1285 ◽  
Author(s):  
Eider Núñez ◽  
Arantza Muguruza-Montero ◽  
Alvaro Villarroel
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Therapeutic Potential ◽  
Structural Information ◽  
Lipid Binding ◽  
Channel Structure ◽  
Extracellular Medium ◽  
Alpha Helices ◽  
Functional Studies ◽  
Direct Binding

Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca2+ signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K+, and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca2+. Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential.

scholarly journals Computational Ion Channel Research: from the Application of Artificial Intelligence to Molecular Dynamics Simulations.

2020 ◽  
Vol 55 (S3) ◽  
pp. 14-45
Keyword(s):  
Artificial Intelligence ◽  
Molecular Dynamics ◽  
Ion Channels ◽  
Ion Channel ◽  
Computational Methods ◽  
Homology Modelling ◽  
Channel Structure ◽  
Learning Approaches ◽  
Qsar Analysis ◽  
Wide Range

Although ion channels are crucial in many physiological processes and constitute an important class of drug targets, much is still unclear about their function and possible malfunctions that lead to diseases. In recent years, computational methods have evolved into important and invaluable approaches for studying ion channels and their functions. This is mainly due to their demanding mechanism of action where a static picture of an ion channel structure is often insufficient to fully understand the underlying mechanism. Therefore, the use of computational methods is as important as chemical-biological based experimental methods for a better understanding of ion channels. This review provides an overview on a variety of computational methods and software specific to the field of ion-channels. Artificial intelligence (or more precisely machine learning) approaches are applied for the sequence-based prediction of ion channel family, or topology of the transmembrane region. In case sufficient data on ion channel modulators is available, these methods can also be applied for quantitative structureactivity relationship (QSAR) analysis. Molecular dynamics (MD) simulations combined with computational molecular design methods such as docking can be used for analysing the function of ion channels including ion conductance, different conformational states, binding sites and ligand interactions, and the influence of mutations on their function. In the absence of a three-dimensional protein structure, homology modelling can be applied to create a model of your ion channel structure of interest. Besides highlighting a wide range of successful applications, we will also provide a basic introduction to the most important computational methods and discuss best practices to get a rough idea of possible applications and risks.

scholarly journals Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels

2021 ◽  
Vol 14 ◽  
Author(s):  
Deepanjali Dwivedi ◽  
Upinder S. Bhalla
Keyword(s):  
Ion Channels ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Brain Regions ◽  
Channel Activity ◽  
Current Review ◽  
Cellular Excitability ◽  
M Channels ◽  
Neuronal Functions

SK, HCN, and M channels are medium afterhyperpolarization (mAHP)-mediating ion channels. The three channels co-express in various brain regions, and their collective action strongly influences cellular excitability. However, significant diversity exists in the expression of channel isoforms in distinct brain regions and various subcellular compartments, which contributes to an equally diverse set of specific neuronal functions. The current review emphasizes the collective behavior of the three classes of mAHP channels and discusses how these channels function together although they play specialized roles. We discuss the biophysical properties of these channels, signaling pathways that influence the activity of the three mAHP channels, various chemical modulators that alter channel activity and their therapeutic potential in treating various neurological anomalies. Additionally, we discuss the role of mAHP channels in the pathophysiology of various neurological diseases and how their modulation can alleviate some of the symptoms.

scholarly journals Cryo-EM structures of the DCPIB-inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs

2018 ◽  
Author(s):  
David M. Kern ◽  
SeCheol Oh ◽  
Richard K. Hite ◽  
Stephen G. Brohawn
Keyword(s):  
Lipid Bilayers ◽  
Critical Role ◽  
Anion Channel ◽  
Lipid Binding ◽  
Channel Structure ◽  
Anion Channels ◽  
Cryo Electron Microscopy ◽  
Lipid Nanodiscs ◽  
Insight Into

AbstractHypoosmotic conditions activate volume-regulated anion channels in vertebrate cells. These channels are formed by leucine-rich repeat-containing protein 8 (LRRC8) family members and contain LRRC8A in homo- or hetero-hexameric assemblies. Here we present single-particle cryo-electron microscopy structures of LRRC8A in complex with the inhibitor DCPIB reconstituted in lipid nanodiscs. DCPIB plugs the channel like a cork in a bottle - binding in the extracellular selectivity filter and sterically occluding ion conduction. Constricted and expanded structures reveal coupled dilation of cytoplasmic LRRs and the channel pore, suggesting a mechanism for channel gating by internal stimuli. Conformational and symmetry differences between LRRC8A structures determined in detergent micelles and lipid bilayers related to reorganization of intersubunit lipid binding sites demonstrate a critical role for the membrane in determining channel structure. These results provide insight into LRRC8 gating and inhibition and the role of lipids in the structure of an ionic-strength sensing ion channel.

Inhibition of Na+/H+exchange stimulates CCK secretion in STC-1 cells

1998 ◽  
Vol 275 (4) ◽  
pp. G689-G695
Author(s):  
Veronica Prpic ◽  
J. Gregory Fitz ◽  
Yu Wang ◽  
John R. Raymond ◽  
Maria N. Garnovskaya ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Cell Metabolism ◽  
Hormone Secretion ◽  
Membrane Depolarization ◽  
Ph Sensitive ◽  
Extracellular Medium ◽  
Voltage Dependent ◽  
Effects Of Ph ◽  
Intracellular Ca ◽  
Cck Release

It has been demonstrated that K+ channel regulation of membrane potential is critical for control of CCK secretion. Because certain K+ channels are pH sensitive, it was postulated that pH affects K+channel activity in the CCK-secreting cell line STC-1 and may participate in regulating CCK secretion. The present study examines the role of electroneutral Na+/H+exchange on extracellular acidification and hormone secretion. Treatment of STC-1 cells with the amiloride analog ethylisopropyl amiloride (EIPA) to inhibit Na+/H+exchange inhibited Na+-dependent H+ efflux and increased basal CCK secretion. Substituting choline for NaCl in the extracellular medium elevated basal intracellular Ca2+concentration and stimulated CCK release. Stimulatory effects on hormone secretion were blocked by the L-type Ca2+ channel blocker diltiazem, indicating that secretion was dependent on the influx of extracellular Ca2+. To determine whether the effects of EIPA and Na+ depletion were due to membrane depolarization, we tested graded KCl concentrations. The ability of EIPA to increase CCK secretion was inhibited by depolarization induced by 10–50 mM KCl in the bath. Maneuvers to lower intracellular pH (pHi), including reducing extracellular pH (pHo) to 7.0 or treatment with sodium butyrate, significantly increased CCK secretion. To examine whether pH directly affects membrane K+ permeability, we measured outward currents carried by K+, using whole cell patch techniques. K+ current was significantly inhibited by lowering pHo to 7.0. These effects appear to be mediated through changes in pHi, because intracellular dialysis with acidic solutions nearly eliminated current activity. These results suggest that Na+/H+exchange and membrane potential may be functionally linked, where inhibition of Na+/H+exchange lowers pHi and depolarizes the membrane, perhaps through inhibition of pH-sensitive K+ channels. In turn, K+ channel closure and membrane depolarization open voltage-dependent Ca2+ channels, leading to an increase in cytosolic Ca2+ and CCK release. The effects of pHi on K+ channels may serve as a potent stimulus for hormone secretion, linking cell metabolism and secretory functions.

An NMR study of cellular phosphates and membrane transport in renal proximal tubules

1995 ◽  
Vol 268 (3) ◽  
pp. F375-F384 ◽  
Author(s):  
M. C. Chobanian ◽  
M. E. Anderson ◽  
P. C. Brazy
Keyword(s):  
Membrane Potential ◽  
Membrane Transport ◽  
Basolateral Membrane ◽  
Barium Chloride ◽  
Partial Replacement ◽  
Transport Mechanisms ◽  
Extracellular Medium ◽  
Protein Inhibition ◽  
Nmr Study ◽  
Perifusion System

Technical limitations in the measurement of cellular phosphates have hindered studies of interrelationships between cellular Pi, its transport, and its metabolism in renal proximal tubule (PT) cells. We have developed a noninvasive 31P-nuclear magnetic resonance (NMR) probe-perifusion system to measure cellular Pi and have utilized this system to investigate relationships in canine PT cells between the membrane transport and the cellular content of Pi. With 1.2 mM Pi in the extracellular medium, the cellular Pi content of PT averaged 4.94 +/- 0.55 nmol/mg protein. Inhibition of Pi uptake by removal of extracellular Pi rapidly decreased all cellular phosphate compounds to values that were between 55 and 85% of control. Partial replacement of extracellular Pi (0.4 mM) increased cellular phosphates up to 84-100% of control values. Inhibition of Na(+)-K(+)-adenosinetriphosphatase uptake by the addition of ouabain failed to change either cellular Pi or organic phosphates. Reducing the basolateral membrane potential with the addition of barium chloride increased cellular Pi content by nearly 30%. Maximal contents of cellular Pi and ATP were achieved at 0.4 mM Pi in the presence of an inwardly directed Na+ gradient and at 0.8 mM Pi in its absence. These data indicate that cellular Pi content in canine PT is regulated by Na(+)-dependent and -independent transport mechanisms and by the membrane potential across the basolateral membrane. Lastly, cellular ATP content was found to be directly proportional to the cellular Pi content over a physiological range.

scholarly journals Computational Methods for Structural and Functional Studies of Alzheimer’s Amyloid Ion Channels

2016 ◽  
pp. 251-268 ◽  
Author(s):  
Hyunbum Jang ◽  
Fernando Teran Arce ◽  
Joon Lee ◽  
Alan L. Gillman ◽  
Srinivasan Ramachandran ◽  
...  
Keyword(s):  
Ion Channels ◽  
Computational Methods ◽  
Functional Studies

Ion Channels as G Protein Effectors

Physiology ◽  
1991 ◽  
Vol 6 (4) ◽  
pp. 158-161
Author(s):  
AM Brown
Keyword(s):  
Membrane Potential ◽  
Ion Channels ◽  
Cell Signaling ◽  
G Protein ◽  
G Proteins ◽  
Heterotrimeric G Proteins ◽  
Regulatory Processes ◽  
Functional Implications

Signaling between cells may be accomplished or accompanied by changes in membrane potential. The latter is regulated by ion channels, which are targets for regulatory processes initiated during signaling. Cell signaling frequently involves heterotrimeric G proteins. Evidence that ion channels are G protein effectors and functional implications of such regulation are reviewed.

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