scholarly journals Four drug-sensitive subunits are required for maximal effect of a voltage sensor–targeted KCNQ opener

2018 ◽  
Vol 150 (10) ◽  
pp. 1432-1443 ◽  
Author(s):  
Alice W. Wang ◽  
Michael C. Yau ◽  
Caroline K. Wang ◽  
Nazlee Sharmin ◽  
Runying Y. Yang ◽  
...  
Keyword(s):  
Small Molecule ◽  
Voltage Sensor ◽  
Side Chain ◽  
Maximal Effect ◽  
Single Drug ◽  
Maximal Sensitivity ◽  
Full Complement ◽  
Voltage Sensing Domain ◽  
Voltage Relationship ◽  
Channel Activator

KCNQ2-5 (Kv7.2–Kv7.5) channels are strongly influenced by an emerging class of small-molecule channel activators. Retigabine is the prototypical KCNQ activator that is thought to bind within the pore. It requires the presence of a Trp side chain that is conserved among retigabine-sensitive channels but absent in the retigabine-insensitive KCNQ1 subtype. Recent work has demonstrated that certain KCNQ openers are insensitive to mutations of this conserved Trp, and that their effects are instead abolished or attenuated by mutations in the voltage-sensing domain (VSD). In this study, we investigate the stoichiometry of a VSD-targeted KCNQ2 channel activator, ICA-069673, by forming concatenated channel constructs with varying numbers of drug-insensitive subunits. In homomeric WT KCNQ2 channels, ICA-069673 strongly stabilizes an activated channel conformation, which is reflected in the pronounced deceleration of deactivation and leftward shift of the conductance–voltage relationship. A full complement of four drug-sensitive subunits is required for maximal sensitivity to ICA-069673—even a single drug-insensitive subunit leads to significantly weakened effects. In a companion article (see Yau et al. in this issue), we demonstrate very different stoichiometry for the action of retigabine on KCNQ3, for which a single retigabine-sensitive subunit enables near-maximal effect. Together, these studies highlight fundamental differences in the site and mechanism of activation between retigabine and voltage sensor–targeted KCNQ openers.

scholarly journals One drug-sensitive subunit is sufficient for a near-maximal retigabine effect in KCNQ channels

2018 ◽  
Vol 150 (10) ◽  
pp. 1421-1431 ◽  
Author(s):  
Michael C. Yau ◽  
Robin Y. Kim ◽  
Caroline K. Wang ◽  
Jingru Li ◽  
Tarek Ammar ◽  
...  
Keyword(s):  
Side Chain ◽  
Multiple Drug ◽  
Maximal Effect ◽  
Large Shift ◽  
Kcnq Channels ◽  
Kv Channel ◽  
Solution Exchange ◽  
Channel Opener ◽  
Hyperpolarizing Shift ◽  
Voltage Relationship

Retigabine is an antiepileptic drug and the first voltage-gated potassium (Kv) channel opener to be approved for human therapeutic use. Retigabine is thought to interact with a conserved Trp side chain in the pore of KCNQ2–5 (Kv7.2–7.5) channels, causing a pronounced hyperpolarizing shift in the voltage dependence of activation. In this study, we investigate the functional stoichiometry of retigabine actions by manipulating the number of retigabine-sensitive subunits in concatenated KCNQ3 channel tetramers. We demonstrate that intermediate retigabine concentrations cause channels to exhibit biphasic conductance–voltage relationships rather than progressive concentration-dependent shifts. This suggests that retigabine can exert its effects in a nearly “all-or-none” manner, such that channels exhibit either fully shifted or unshifted behavior. Supporting this notion, concatenated channels containing only a single retigabine-sensitive subunit exhibit a nearly maximal retigabine effect. Also, rapid solution exchange experiments reveal delayed kinetics during channel closure, as retigabine dissociates from channels with multiple drug-sensitive subunits. Collectively, these data suggest that a single retigabine-sensitive subunit can generate a large shift of the KCNQ3 conductance–voltage relationship. In a companion study (Wang et al. 2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812014), we contrast these findings with the stoichiometry of a voltage sensor-targeted KCNQ channel opener (ICA-069673), which requires four drug-sensitive subunits for maximal effect.

scholarly journals Upgraded molecular models of the human KCNQ1 potassium channel

2019 ◽  
Author(s):  
Georg Kuenze ◽  
Amanda M. Duran ◽  
Hope Woods ◽  
Kathryn R. Brewer ◽  
Eli Fritz McDonald ◽  
...  
Keyword(s):  
Voltage Sensor ◽  
Cardiac Action Potential ◽  
Molecular Models ◽  
Loss Of Function ◽  
Voltage Sensing ◽  
Common Cause ◽  
Cardiac Action ◽  
Electrical Impulses ◽  
Voltage Sensing Domain ◽  
Pore Domain

AbstractThe voltage-gated potassium channel KCNQ1 (KV7.1) assembles with the KCNE1 accessory protein to generate the slow delayed rectifier current, IKS, which is critical for membrane repolarization as part of the cardiac action potential. Loss-of-function (LOF) mutations in KCNQ1 are the most common cause of congenital long QT syndrome (LQTS), type 1 LQTS, an inherited genetic predisposition to cardiac arrhythmia and sudden cardiac death. A detailed structural understanding of KCNQ1 is needed to elucidate the molecular basis for KCNQ1 LOF in disease and to enable structure-guided design of new anti-arrhythmic drugs. In this work, advanced structural models of human KCNQ1 in the resting/closed and activated/open states were developed by Rosetta homology modeling guided by newly available experimentally-based templates: X. leavis KCNQ1 and resting voltage sensor structures. Using molecular dynamics (MD) simulations, the models’ capability to describe experimentally established channel properties including state-dependent voltage sensor gating charge interactions and pore conformations, PIP2 binding sites, and voltage sensor – pore domain interactions were validated. Rosetta energy calculations were applied to assess the models’ utility in interpreting mutation-evoked KCNQ1 dysfunction by predicting the change in protein thermodynamic stability for 50 characterized KCNQ1 variants with mutations located in the voltage-sensing domain. Energetic destabilization was successfully predicted for folding-defective KCNQ1 LOF mutants whereas wild type-like mutants had no significant energetic frustrations, which supports growing evidence that mutation-induced protein destabilization is an especially common cause of KCNQ1 dysfunction. The new KCNQ1 Rosetta models provide helpful tools in the study of the structural mechanisms of KCNQ1 function and can be used to generate structure-based hypotheses to explain KCNQ1 dysfunction.Author SummaryCardiac rhythm is maintained by synchronized electrical impulses conducted throughout the heart. The potassium ion channel KCNQ1 is important for the repolarization phase of the cardiac action potential that underlies these electrical impulses. Heritable mutations in KCNQ1 can lead to channel loss-of-function (LOF) and predisposition to a life-threatening cardiac arrhythmia. Knowledge of the three-dimensional structure of KCNQ1 is important to understand how mutations lead to LOF and to support structurally-guided design of new anti-arrhythmic drugs. In this work, we present the development and validation of molecular models of human KCNQ1 inferred by homology from the structure of frog KCNQ1. Models were developed for the open channel state in which potassium ions can pass through the channel and the closed state in which the channel is not conductive. Using molecular dynamics simulations, interactions in the voltage-sensing and pore domain of KCNQ1 and with the membrane lipid PIP2 were analyzed. Energy calculations for KCNQ1 mutations in the voltage-sensing domain reveled that most of the mutations that lead to LOF cause energetic destabilization of the KCNQ1 protein. The results support both the utility of the new models and growing evidence that mutation-induced protein destabilization is a common cause of KCNQ1 dysfunction.

scholarly journals Structural and Functional Role of the Extracellular S5-P Linker in the HERG Potassium Channel

2002 ◽  
Vol 120 (5) ◽  
pp. 723-737 ◽  
Author(s):  
Jie Liu ◽  
Mei Zhang ◽  
Min Jiang ◽  
Gea-Ny Tseng
Keyword(s):  
Functional Role ◽  
Function Analysis ◽  
Voltage Sensor ◽  
Herg Channel ◽  
Side Chain ◽  
Voltage Sensitivity ◽  
Fast Kinetics ◽  
Channel Function ◽  
Outer Vestibule

C-type inactivation in the HERG channel is unique among voltage-gated K channels in having extremely fast kinetics and strong voltage sensitivity. This suggests that HERG may have a unique outer mouth structure (where conformational changes underlie C-type inactivation), and/or a unique communication between the outer mouth and the voltage sensor. We use cysteine-scanning mutagenesis and thiol-modifying reagents to probe the structural and functional role of the S5-P (residues 571–613) and P-S6 (residues 631–638) linkers of HERG that line the outer vestibule of the channel. Disulfide formation involving introduced cysteine side chains or modification of side chain properties at “high-impact” positions produces a common mutant phenotype: disruption of C-type inactivation, reduction of K+ selectivity, and hyperpolarizing shift in the voltage-dependence of activation. In particular, we identify 15 consecutive positions in the middle of the S5-P linker (583–597) where side chain modification has marked impact on channel function. Analysis of the degrees of mutation-induced perturbation in channel function along 583–597 reveals an α-helical periodicity. Furthermore, the effects of MTS modification suggest that the NH2-terminal of this segment (position 584) may be very close to the pore entrance. We propose a structural model for the outer vestibule of the HERG channel, in which the 583–597 segment forms an α-helix. With the NH2 terminus of this helix sitting at the edge of the pore entrance, the length of the helix (∼20 Å) allows its other end to reach and interact with the voltage-sensing domain. Therefore, the “583–597 helix” in the S5-P linker of the HERG channel serves as a bridge of communication between the outer mouth and the voltage sensor, that may make important contribution to the unique C-type inactivation phenotype.

Side chain engineering in DTBDT-based small molecules for efficient organic photovoltaics

Nanoscale ◽  
2019 ◽  
Vol 11 (29) ◽  
pp. 13845-13852 ◽  
Author(s):  
Jisu Hong ◽  
Ji Young Choi ◽  
Kyunghun Kim ◽  
Nam-Suk Lee ◽  
Jiqiang Li ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Organic Photovoltaics ◽  
Side Chain ◽  
Solvent Vapor ◽  
Vapor Annealing ◽  
Solvent Vapor Annealing

A new small-molecule donor with a DTBDT core exhibits apposite blend morphologies and a maximum PCE of 9.18% by side chain engineering and solvent vapor annealing.

Antibacterial activity of cationic polymers: side-chain or main-chain type?

2018 ◽  
Vol 9 (37) ◽  
pp. 4611-4616 ◽  
Author(s):  
Jiangna Guo ◽  
Jing Qin ◽  
Yongyuan Ren ◽  
Bin Wang ◽  
Hengqing Cui ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Small Molecule ◽  
Quaternary Ammonium ◽  
Main Chain ◽  
Side Chain ◽  
Cationic Polymers ◽  
Cationic Compounds ◽  
Chain Type

Imidazolium (Im), quaternary ammonium (Qa), and 1,4-diazabicyclo[2.2.2]octane-1,4-diium (DABCO-diium) cation-based small molecule cationic compounds and their corresponding side-chain/main-chain cationic polymers were synthesized.

Isophthalate-Based Room Temperature Phosphorescence: From Small Molecule to Side-Chain Jacketed Liquid Crystalline Polymer

2019 ◽  
Vol 52 (6) ◽  
pp. 2495-2503 ◽  
Author(s):  
Yan-Fang Zhang ◽  
Yue-Chao Wang ◽  
Xiao-Song Yu ◽  
Yang Zhao ◽  
Xiang-Kui Ren ◽  
...  
Keyword(s):  
Small Molecule ◽  
Liquid Crystalline Polymer ◽  
Liquid Crystalline ◽  
Room Temperature ◽  
Crystalline Polymer ◽  
Side Chain ◽  
Room Temperature Phosphorescence

scholarly journals Bipolar switching by HCN voltage sensor underlies hyperpolarization activation

2018 ◽  
Vol 116 (2) ◽  
pp. 670-678 ◽  
Author(s):  
John Cowgill ◽  
Vadim A. Klenchin ◽  
Claudia Alvarez-Baron ◽  
Debanjan Tewari ◽  
Alexander Blair ◽  
...  
Keyword(s):  
Voltage Sensor ◽  
Hcn Channels ◽  
Structural Element ◽  
Bipolar Switching ◽  
Primary Determinant ◽  
Full Complement ◽  
Common Principle ◽  
Pore Opening ◽  
Voltage Gated Ion Channels ◽  
Common Architecture

Despite sharing a common architecture with archetypal voltage-gated ion channels (VGICs), hyperpolarization- and cAMP-activated ion (HCN) channels open upon hyperpolarization rather than depolarization. The basic motions of the voltage sensor and pore gates are conserved, implying that these domains are inversely coupled in HCN channels. Using structure-guided protein engineering, we systematically assembled an array of mosaic channels that display the full complement of voltage-activation phenotypes observed in the VGIC superfamily. Our studies reveal that the voltage sensor of the HCN channel has an intrinsic ability to drive pore opening in either direction and that the extra length of the HCN S4 is not the primary determinant for hyperpolarization activation. Tight interactions at the HCN voltage sensor–pore interface drive the channel into an hERG-like inactivated state, thereby obscuring its opening upon depolarization. This structural element in synergy with the HCN cyclic nucleotide-binding domain and specific interactions near the pore gate biases the channel toward hyperpolarization-dependent opening. Our findings reveal an unexpected common principle underpinning voltage gating in the VGIC superfamily and identify the essential determinants of gating polarity.

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