scholarly journals An electrostatic potassium channel opener targeting the final voltage sensor transition

2011 ◽  
Vol 137 (6) ◽  
pp. 563-577 ◽  
Author(s):  
Sara I. Börjesson ◽  
Fredrik Elinder
Keyword(s):  
Ion Channels ◽  
Epileptic Seizures ◽  
Voltage Sensor ◽  
K Channel ◽  
Voltage Gated ◽  
Pharmacological Mechanism ◽  
Channel Opening ◽  
Channel Surface ◽  
Future Drug ◽  
Voltage Gated Ion Channels

Free polyunsaturated fatty acids (PUFAs) modulate the voltage dependence of voltage-gated ion channels. As an important consequence thereof, PUFAs can suppress epileptic seizures and cardiac arrhythmia. However, molecular details for the interaction between PUFA and ion channels are not well understood. In this study, we have localized the site of action for PUFAs on the voltage-gated Shaker K channel by introducing positive charges on the channel surface, which potentiated the PUFA effect. Furthermore, we found that PUFA mainly affects the final voltage sensor movement, which is closely linked to channel opening, and that specific charges at the extracellular end of the voltage sensor are critical for the PUFA effect. Because different voltage-gated K channels have different charge profiles, this implies channel-specific PUFA effects. The identified site and the pharmacological mechanism will potentially be very useful in future drug design of small-molecule compounds specifically targeting neuronal and cardiac excitability.

scholarly journals Drug-induced ion channel opening tuned by the voltage sensor charge profile

2014 ◽  
Vol 143 (2) ◽  
pp. 173-182 ◽  
Author(s):  
Nina E. Ottosson ◽  
Sara I. Liin ◽  
Fredrik Elinder
Keyword(s):  
Small Molecule ◽  
Voltage Sensor ◽  
K Channel ◽  
Detailed Knowledge ◽  
Drug Induced ◽  
New Class ◽  
Channel Opening ◽  
Future Drug ◽  
Small Molecule Compound ◽  
Voltage Gated Ion Channels

Polyunsaturated fatty acids modulate the voltage dependence of several voltage-gated ion channels, thereby being potent modifiers of cellular excitability. Detailed knowledge of this molecular mechanism can be used in designing a new class of small-molecule compounds against hyperexcitability diseases. Here, we show that arginines on one side of the helical K-channel voltage sensor S4 increased the sensitivity to docosahexaenoic acid (DHA), whereas arginines on the opposing side decreased this sensitivity. Glutamates had opposite effects. In addition, a positively charged DHA-like molecule, arachidonyl amine, had opposite effects to the negatively charged DHA. This suggests that S4 rotates to open the channel and that DHA electrostatically affects this rotation. A channel with arginines in positions 356, 359, and 362 was extremely sensitive to DHA: 70 µM DHA at pH 9.0 increased the current >500 times at negative voltages compared with wild type (WT). The small-molecule compound pimaric acid, a novel Shaker channel opener, opened the WT channel. The 356R/359R/362R channel drastically increased this effect, suggesting it to be instrumental in future drug screening.

scholarly journals Cryo-EM structure of the KvAP channel reveals a non-domain-swapped voltage sensor topology

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Xiao Tao ◽  
Roderick MacKinnon
Keyword(s):  
Ion Channels ◽  
Conformational Changes ◽  
Voltage Sensor ◽  
Structural Domains ◽  
Structural Class ◽  
Voltage Sensors ◽  
Voltage Gated ◽  
Voltage Dependent ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

Conductance in voltage-gated ion channels is regulated by membrane voltage through structural domains known as voltage sensors. A single structural class of voltage sensor domain exists, but two different modes of voltage sensor attachment to the pore occur in nature: domain-swapped and non-domain-swapped. Since the more thoroughly studied Kv1-7, Nav and Cav channels have domain-swapped voltage sensors, much less is known about non-domain-swapped voltage-gated ion channels. In this paper, using cryo-EM, we show that KvAP from Aeropyrum pernix has non-domain-swapped voltage sensors as well as other unusual features. The new structure, together with previous functional data, suggests that KvAP and the Shaker channel, to which KvAP is most often compared, probably undergo rather different voltage-dependent conformational changes when they open.

scholarly journals Transfer of Voltage Independence from a Rat Olfactory Channel to the Drosophila Ether-à-go-go K+ Channel

1997 ◽  
Vol 109 (3) ◽  
pp. 301-311 ◽  
Author(s):  
Chih-Yung Tang ◽  
Diane M. Papazian
Keyword(s):  
Cyclic Nucleotide ◽  
Voltage Sensor ◽  
K Channel ◽  
Voltage Range ◽  
Voltage Gated ◽  
Cyclic Nucleotide Gated Channels ◽  
Voltage Dependent ◽  
Relative Stabilization ◽  
Voltage Gated Ion Channels ◽  
S4 Segment

The S4 segment is an important part of the voltage sensor in voltage-gated ion channels. Cyclic nucleotide-gated channels, which are members of the superfamily of voltage-gated channels, have little inherent sensitivity to voltage despite the presence of an S4 segment. We made chimeras between a voltage-independent rat olfactory channel (rolf) and the voltage-dependent ether-à-go-go K+ channel (eag) to determine the basis of their divergent gating properties. We found that the rolf S4 segment can support a voltage-dependent mechanism of activation in eag, suggesting that rolf has a potentially functional voltage sensor that is silent during gating. In addition, we found that the S3-S4 loop of rolf increases the relative stability of the open conformation of eag, effectively converting eag into a voltage-independent channel. A single charged residue in the loop makes a significant contribution to the relative stabilization of the open state in eag. Our data suggest that cyclic nucleotide-gated channels such as rolf contain a voltage sensor which, in the physiological voltage range, is stabilized in an activated conformation that is permissive for pore opening.

The moving parts of voltage-gated ion channels

1998 ◽  
Vol 31 (3) ◽  
pp. 239-295 ◽  
Author(s):  
GARY YELLEN
Keyword(s):  
Ion Channels ◽  
Basic Structure ◽  
Voltage Sensor ◽  
Site Directed Mutagenesis ◽  
Charge Movement ◽  
Voltage Gated ◽  
Activation Gate ◽  
Activation Gating ◽  
Voltage Gated Ion Channels ◽  
Moving Parts

Ion channels, like many other proteins, have moving parts that perform useful functions. The channel proteins contain an aqueous, ion-selective pore that crosses the plasma membrane, and they use a number of distinct ‘gating’ mechanisms to open and close this pore in response to biological stimuli such as the binding of a ligand or a change in the transmembrane voltage.This review is written at a watershed in our understanding of ion channels.1. INTRODUCTION 2401.1 Basic structure of voltage-activated channels 2411.2 What are the physical motions of the channel protein during gating? 2431.3 Gating involves several distinct mechanisms of activation and inactivation 2462. ACTIVATION GATING 2462.1 Early evidence for an activation gate at the intracellular mouth 2472.1.1 Open channel blockade 2472.1.2 The ‘ foot-in-the-door’ effect 2492.1.3 Trapping of blockers behind closed activation gates 2492.2 Site-directed mutagenesis and the difficulty of inferring structural roles from functional effects 2502.3 State-dependent cysteine modification as a reporter of position and motion 2512.4 Localization of activation gating 2542.4.1 The trapping cavity 2542.4.2 The activation gate 2552.4.3 Is there more than one site of activation gating? 2583. INACTIVATION GATING 2593.1 Ball-and-chain (N-type) inactivation 2613.1.1 Nature of the ‘ball’ – a tethered blocking particle 2623.1.2 The ball receptor 2633.1.3 The chain 2643.1.4 Variations on the N-type inactivation theme: multiple balls, foreign balls, anti-balls 2653.2 C-type inactivation 2663.2.1 C-type inactivation and the outer mouth of the K+channel 2663.2.2 The selectivity filter participates in C-type inactivation 2673.2.3 A consistent structural picture of C-type inactivation 2693.3 By what mechanism do other voltage-gated channels inactivate? 2724. THE VOLTAGE SENSOR 2734.1 Quantitative principles of voltage-dependent gating 2764.2 S4 (and its neighbours) as the principal voltage sensor 2774.2.1 Mutational effects on voltage-dependence and charge movement 2774.2.2 Evidence for the translocation of S4 2794.2.3 Real-time monitoring of S4motion by fluorescence 2824.3 Coupling between the voltage sensor and gating 2835. CONCLUSION 2846. ACKNOWLEDGEMENTS 2877. REFERENCES 287

scholarly journals Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors

2018 ◽  
Vol 150 (8) ◽  
pp. 1215-1230 ◽  
Author(s):  
Sara I. Liin ◽  
Per-Eric Lund ◽  
Johan E. Larsson ◽  
Johan Brask ◽  
Björn Wallner ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Action Potential ◽  
Ion Channel ◽  
Potassium Channel ◽  
Voltage Sensor ◽  
Pharmaceutical Drugs ◽  
Voltage Gated ◽  
Channel Opening ◽  
Ion Conducting ◽  
Voltage Gated Ion Channels

Voltage-gated ion channels are key molecules for the generation of cellular electrical excitability. Many pharmaceutical drugs target these channels by blocking their ion-conducting pore, but in many cases, channel-opening compounds would be more beneficial. Here, to search for new channel-opening compounds, we screen 18,000 compounds with high-throughput patch-clamp technology and find several potassium-channel openers that share a distinct biaryl-sulfonamide motif. Our data suggest that the negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although we show here that biaryl-sulfonamide compounds open a potassium channel, they have also been reported to block sodium and calcium channels. However, because they inactivate voltage-gated sodium channels by promoting activation of one voltage sensor, we suggest that, despite different effects on the channel gates, the biaryl-sulfonamide motif is a general ion-channel activator motif. Because these compounds block action potential–generating sodium and calcium channels and open an action potential–dampening potassium channel, they should have a high propensity to reduce excitability. This opens up the possibility to build new excitability-reducing pharmaceutical drugs from the biaryl-sulfonamide scaffold.

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