scholarly journals Domain–domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Mark A Zaydman ◽  
Marina A Kasimova ◽  
Kelli McFarland ◽  
Zachary Beller ◽  
Panpan Hou ◽  
...  
Keyword(s):  
Ion Channels ◽  
Physiological Role ◽  
Specific Expression ◽  
Electrical Currents ◽  
Voltage Gated ◽  
State Dependent ◽  
Domain Interactions ◽  
Voltage Gated Ion Channels ◽  
Hormonal Release

Voltage-gated ion channels generate electrical currents that control muscle contraction, encode neuronal information, and trigger hormonal release. Tissue-specific expression of accessory (β) subunits causes these channels to generate currents with distinct properties. In the heart, KCNQ1 voltage-gated potassium channels coassemble with KCNE1 β-subunits to generate the IKs current (<xref ref-type="bibr" rid="bib3">Barhanin et al., 1996</xref>; <xref ref-type="bibr" rid="bib57">Sanguinetti et al., 1996</xref>), an important current for maintenance of stable heart rhythms. KCNE1 significantly modulates the gating, permeation, and pharmacology of KCNQ1 (<xref ref-type="bibr" rid="bib77">Wrobel et al., 2012</xref>; <xref ref-type="bibr" rid="bib66">Sun et al., 2012</xref>; <xref ref-type="bibr" rid="bib1">Abbott, 2014</xref>). These changes are essential for the physiological role of IKs (<xref ref-type="bibr" rid="bib62">Silva and Rudy, 2005</xref>); however, after 18 years of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent interactions that functionally couple the voltage-sensing domains (VSDs) to the pore.

scholarly journals Large Neurohypophysial Varicosities Amplify Action Potentials: Results from Numerical Simulations

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2829-2836 ◽  
Author(s):  
C. Brad Bennett ◽  
Martin Muschol
Keyword(s):  
Ion Channels ◽  
Numerical Simulations ◽  
Action Potentials ◽  
Calcium Influx ◽  
Physiological Role ◽  
Nonlinear Dependence ◽  
Voltage Gated ◽  
Herring Bodies ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

Axons in the neurohypophysis are known for their “beads on a string” morphology, with numerous in-line secretory swellings lined up along the axon cable. A significant fraction of these secretory swellings, called Herring bodies, is large enough to serve as an identifying feature of the neural lobe in histological sections. Little is known about the physiological role such large axonal swellings might play in neuroendocrine physiology. Using numerical simulations, we have investigated whether large in-line varicosities affect the waveform and propagation of action potentials (APs) along neurohypophysial axons. Due to the strong nonlinear dependence of calcium influx on AP waveforms, such modulation would inevitably affect neuroendocrine release. The parameters for our numerical simulations were matched to established properties of voltage-gated ion channels in neurohypophysial swellings. We find that even a single in-line varicosity can severely depress AP waveforms far upstream in the axonal cable. In contrast, AP depolarization within varicosities becomes amplified. Amplification within varicosities varies in a nontrivial manner with varicosity dimensions, and is most pronounced for diameters close to those of Herring bodies. Overall, we find that large axonal varicosities significantly modulate AP waveforms and their propagation, and do so over large distances. Varicosity size is the main determinant for the observed AP amplification, with the kinetics of voltage-gated ion channels playing a noticeable but secondary role. Our results imply that large varicosities are sites of enhanced hormone release, suggesting that small and large varicosities target different neurohypophysial structures.

scholarly journals Optical electrophysiology for probing function and pharmacology of voltage-gated ion channels

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Hongkang Zhang ◽  
Elaine Reichert ◽  
Adam E Cohen
Keyword(s):  
Ion Channels ◽  
Voltage Clamp ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Inhibitory Effect ◽  
Optical Measurements ◽  
Voltage Gated ◽  
State Dependent ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

Voltage-gated ion channels mediate electrical dynamics in excitable tissues and are an important class of drug targets. Channels can gate in sub-millisecond timescales, show complex manifolds of conformational states, and often show state-dependent pharmacology. Mechanistic studies of ion channels typically involve sophisticated voltage-clamp protocols applied through manual or automated electrophysiology. Here, we develop all-optical electrophysiology techniques to study activity-dependent modulation of ion channels, in a format compatible with high-throughput screening. Using optical electrophysiology, we recapitulate many voltage-clamp protocols and apply to Nav1.7, a channel implicated in pain. Optical measurements reveal that a sustained depolarization strongly potentiates the inhibitory effect of PF-04856264, a Nav1.7-specific blocker. In a pilot screen, we stratify a library of 320 FDA-approved compounds by binding mechanism and kinetics, and find close concordance with patch clamp measurements. Optical electrophysiology provides a favorable tradeoff between throughput and information content for studies of NaV channels, and possibly other voltage-gated channels.

scholarly journals Opening TRPP2 (PKD2L1) requires the transfer of gating charges

2019 ◽  
Vol 116 (31) ◽  
pp. 15540-15549 ◽  
Author(s):  
Leo C. T. Ng ◽  
Thuy N. Vien ◽  
Vladimir Yarov-Yarovoy ◽  
Paul G. DeCaen
Keyword(s):  
Ion Channels ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Voltage Gated ◽  
State Dependent ◽  
Transient Receptor ◽  
Voltage Gated Ion Channels ◽  
Gating Charges ◽  
Gated Ion Channels

The opening of voltage-gated ion channels is initiated by transfer of gating charges that sense the electric field across the membrane. Although transient receptor potential ion channels (TRP) are members of this family, their opening is not intrinsically linked to membrane potential, and they are generally not considered voltage gated. Here we demonstrate that TRPP2, a member of the polycystin subfamily of TRP channels encoded by the PKD2L1 gene, is an exception to this rule. TRPP2 borrows a biophysical riff from canonical voltage-gated ion channels, using 2 gating charges found in its fourth transmembrane segment (S4) to control its conductive state. Rosetta structural prediction demonstrates that the S4 undergoes ∼3- to 5-Å transitional and lateral movements during depolarization, which are coupled to opening of the channel pore. Here both gating charges form state-dependent cation–π interactions within the voltage sensor domain (VSD) during membrane depolarization. Our data demonstrate that the transfer of a single gating charge per channel subunit is requisite for voltage, temperature, and osmotic swell polymodal gating of TRPP2. Taken together, we find that irrespective of stimuli, TRPP2 channel opening is dependent on activation of its VSDs.

scholarly journals Analysis of Single Nucleotide Polymorphisms in human Voltage-Gated Ion Channels

2018 ◽  
Author(s):  
Katerina C. Nastou ◽  
Michail A. Batskinis ◽  
Zoi I. Litou ◽  
Stavros J. Hamodrakas ◽  
Vassiliki A. Iconomidou
Keyword(s):  
Ion Channels ◽  
Single Nucleotide Polymorphisms ◽  
Nucleotide Polymorphisms ◽  
Topological Information ◽  
Single Nucleotide ◽  
Voltage Gated ◽  
Arginine Residues ◽  
Voltage Gated Ion Channels ◽  
Gated Ion Channels

AbstractVoltage-Gated Ion Channels (VGICs) are one of the largest groups of transmembrane proteins. Due to their major role in the generation and propagation of electrical signals, VGICs are considered important from a medical viewpoint and their dysfunction is often associated with a group of diseases known as “Channelopathies”. We identified disease associated mutations and polymorphisms in these proteins through mapping missense Single Nucleotide Polymorphisms (SNPs) from the UniProt and ClinVar databases on their amino acid sequence, taking into consideration their special topological and functional characteristics. Statistical analysis revealed that disease associated SNPs are mostly found in the Voltage Sensor Domain – and especially at its fourth transmembrane segment (S4) – and in the Pore Loop. Both these regions are extremely important for the activation and ion conductivity of VGICs. Moreover, amongst the most frequently observed mutations are those of arginine to glutamine, to histidine or to cysteine, which can probably be attributed to the extremely important role of arginine residues in the regulation of membrane potential in these proteins. We suggest that topological information in combination with genetic variation data can contribute towards a better evaluation of the effect of currently unclassified mutations in VGICs. It is hoped that potential associations with certain disease phenotypes will be revealed in the future, with the use of similar approaches.

scholarly journals Mining recent brain proteomic databases for ion channel phosphosite nuggets

2010 ◽  
Vol 137 (1) ◽  
pp. 3-16 ◽  
Author(s):  
Oscar Cerda ◽  
Je-Hyun Baek ◽  
James S. Trimmer
Keyword(s):  
Ion Channels ◽  
Ion Channel ◽  
Mammalian Brain ◽  
Phosphorylation Sites ◽  
Dynamic Regulation ◽  
Voltage Gated ◽  
Voltage Gated Ion Channels ◽  
Α Subunits

Voltage-gated ion channels underlie electrical activity of neurons and are dynamically regulated by diverse cell signaling pathways that alter their phosphorylation state. Recent global mass spectrometric–based analyses of the mouse brain phosphoproteome have yielded a treasure trove of new data as to the extent and nature of phosphorylation of numerous ion channel principal or α subunits in mammalian brain. Here we compile and review data on 347 phosphorylation sites (261 unique) on 42 different voltage-gated ion channel α subunits that were identified in these recent studies. Researchers in the ion channel field can now begin to explore the role of these novel in vivo phosphorylation sites in the dynamic regulation of the localization, activity, and expression of brain ion channels through multisite phosphorylation of their principal subunits.

scholarly journals Brevetoxin and Conotoxin Interactions with Single-Domain Voltage-Gated Sodium Channels from a Diatom and Coccolithophore

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 140
Author(s):  
Ping Yates ◽  
Julie A. Koester ◽  
Alison R. Taylor
Keyword(s):  
Ion Channels ◽  
Sodium Channels ◽  
Single Domain ◽  
Marine Diatom ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Steady State Inactivation ◽  
Outer Pore ◽  
Voltage Gated Ion Channels

The recently characterized single-domain voltage-gated ion channels from eukaryotic protists (EukCats) provide an array of novel channel proteins upon which to test the pharmacology of both clinically and environmentally relevant marine toxins. Here, we examined the effects of the hydrophilic µ-CTx PIIIA and the lipophilic brevetoxins PbTx-2 and PbTx-3 on heterologously expressed EukCat ion channels from a marine diatom and coccolithophore. Surprisingly, none of the toxins inhibited the peak currents evoked by the two EukCats tested. The lack of homology in the outer pore elements of the channel may disrupt the binding of µ-CTx PIIIA, while major structural differences between mammalian sodium channels and the C-terminal domains of the EukCats may diminish interactions with the brevetoxins. However, all three toxins produced significant negative shifts in the voltage dependence of activation and steady state inactivation, suggesting alternative and state-dependent binding conformations that potentially lead to changes in the excitability of the phytoplankton themselves.

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