Role of Hydration and Amino Acid Interactions on the Ion Permeation Mechanism in the hNaV1.5 Channel DOI Creative Commons
Nuria Anguita‐Ortiz, Juan J. Nogueira

Biochemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

This study explores the ion selectivity and conduction mechanisms of hNa

Language: Английский

Structural biology and molecular pharmacology of voltage-gated ion channels DOI
Jian Huang, Xiaojing Pan, Nieng Yan

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 904 - 925

Published: Aug. 5, 2024

Language: Английский

Citations

24
A claudin5-binding peptide enhances the permeability of the blood-brain barrier in vitro DOI Creative Commons

Martina Trevisani,

Alessandro Berselli, Giulio Alberini

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(2)

Published: Jan. 10, 2025

The blood-brain barrier (BBB) maintains brain homeostasis but also prevents most drugs from entering the brain. No paracellular diffusion of solutes is allowed because tight junctions that are made impermeable by expression claudin5 (CLDN5) endothelial cells. possibility regulating BBB permeability in a transient and reversible fashion strong demand for pharmacological treatment diseases. Here, we designed tested short BBB-active peptides, derived CLDN5 extracellular domains CLDN5-binding domain Clostridium perfringens enterotoxin, using robust workflow structural modeling vitro validation techniques. Computational analysis at atom level based on solubility affinity to identified CLDN5-derived peptide not reported previously called f1-C5C2, which was soluble biological media, displayed efficient binding CLDN5, transiently increased permeability. peptidomimetic strategy described here may have potential applications

Language: Английский

Citations

1
Plasticity of the selectivity filter is essential for permeation in lysosomal TPC2 channels DOI Creative Commons
A. Zaki, Süleyman Selim Çınaroğlu, Taufiq Rahman

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(32)

Published: July 29, 2024

Two-pore channels are pathophysiologically important Na + - and Ca 2+ -permeable expressed in lysosomes other acidic organelles. Unlike most ion channels, their permeability is malleable ligand-tuned such that when gated by the signaling lipid PI(3,5)P 2 , they more -selective than mobilizing messenger nicotinic acid adenine dinucleotide phosphate. However, structural basis underlies plasticity single-channel behavior generally remains poorly understood. A recent Cryo-electron microscopy (cryo-EM) structure of TPC2 bound to a proposed open-channel conformation provided an opportunity address this via molecular dynamics (MD) simulation. To our surprise, simulations designed compute conductance through revealed almost no permeation events even at very high transmembrane voltages. However further MD identified spontaneous transition dramatically different selectivity filter involved expansion flip orientation two core asparagine residues. This alternative was remarkably stable allowed flow channel leading estimate good agreement with direct measurements. Furthermore, permeable for over . Our results have ramifications not just understanding control but also broadly terms how discriminate ions.

Language: Английский

Citations

4
Impact of a Terahertz electromagnetic field on the ion permeation of potassium and sodium channels DOI Creative Commons

Zigang Song,

Lingfeng Xue, Qi Ouyang

et al.

Communications Chemistry, Journal Year: 2025, Volume and Issue: 8(1)

Published: April 3, 2025

Ion channels are essential for various physiological processes, and their defects associated with many diseases. Previous research has revealed that a Terahertz electromagnetic field can alter the channel conductance by affecting motion of chemical groups ion channels, hence regulate electric signals neurons. In this study, we conducted molecular dynamics simulations to systematically investigate effects terahertz fields on permeation voltage-gated potassium sodium particularly focusing bound ions in selectivity filters have not been extensively studied previously. Our results identified multiple new characteristic frequencies showed 1.4, 2.2, or 2.9 THz increases permeability Kv1.2, 2.5 48.6 Nav1.5. Such specific directions field, which determined intrinsic oscillation motions permeating filter certain channels. The amplitude positively correlates change permeation. This study demonstrates specifically conductances mechanisms, may carry great potential biomedical applications.

Language: Английский

Citations

0
An all-atom model of the human cardiac sodium channel in a lipid bilayer DOI Creative Commons

Garrett M. Knotts,

Spencer K. Lile,

Edward W. Campbell

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 6, 2024

Voltage-gated sodium channels (NaV) are complex macromolecular proteins that responsible for the initial upstroke of an action potential in excitable cells. Appropriate function is necessary many physiological processes such as heartbeat, voluntary muscle contraction, nerve conduction, and neurological function. Dysfunction can have life-threatening consequences. During past decade, there been significant advancements with ion channel structural characterization by CryoEM, yet descriptions cytosolic components often lacking. Many investigations biophysically characterized reconstituted their interactions. However, extrapolating alterations allosteric communication within intact be challenging. To address this, we developed all-atom model human cardiac (NaV1.5) a lipid bilayer explicit salt water. Our simulations contain poorly predicted AlphaFold lacking CryoEM structures. Leveraging latest Amber force fields (ff19sb Lipid21) water (OPC), our improved protein backbone torsion angles generated information across time (four independent one-microsecond simulations). analysis provided solvent contacts insight into C-Terminal Domain - inactivation gate latch receptor

Language: Английский

Citations

2
Constitutive opening of the Kv7.2 pore activation gate causes KCNQ2 -developmental encephalopathy DOI Creative Commons
Mario Nappi, Giulio Alberini, Alessandro Berselli

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(49)

Published: Nov. 27, 2024

Pathogenic variants in KCNQ2 encoding Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies ( -encephalopathies), both with and without epilepsy. We herein describe the clinical, vitro, silico features of two encephalopathy-causing (A317T, L318V) affecting consecutive residues S 6 activation gate that undergoes large structural rearrangements during pore opening; disease-causing A356T variant KCNQ3 , paralogous to A317T was also investigated. Currents through mutant channels displayed increased density, hyperpolarizing shifts gating, faster slower deactivation kinetics, resistance changes cellular concentrations phosphatidylinositol 4,5-bisphosphate (PIP 2 ), a critical regulator Kv7 function; all these are consistent strong gain-of-function effect. An increase probability single-channel opening, no change membrane abundance or conductance, responsible for observed effects. All-atom molecular dynamics simulations revealed mutations widened inner stabilized constitutively open configuration closed state, minimal effects on conformation. Thus, mutation-induced stabilization is pathogenetic mechanism -related encephalopathies.

Language: Английский

Citations

2
CONSTITUTIVE OPENING OF THE Kv7.2 PORE ACTIVATION GATE CAUSESKCNQ2-DEVELOPMENTAL ENCEPHALOPATHY DOI Open Access
Mario Nappi, Giulio Alberini, Alessandro Berselli

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 21, 2024

ABSTRACT Pathogenic variants in KCNQ2 encoding for Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies ( -encephalopathies), both with and without epilepsy. We herein describe the clinical, vitro silico features of two encephalopathy-causing (A317T, L318V) affecting consecutive residues S 6 activation gate undergoing large structural rearrangements during pore opening. Currents through these mutant channels displayed increased density, hyperpolarizing shifts gating, insensitivity to phosphatidylinositol 4,5-bisphosphate (PIP 2 ), a critical regulator Kv7 function; all are consistent strong gain-of-function effect. An increase single-channel open probability, no change membrane abundance or conductance, was responsible observed effects. All-atoms Molecular Dynamics simulations revealed that mutations widened inner stabilized constitutively configuration closed state, minimal effects on conformation. Thus, PIP -independent stabilization is novel molecular pathogenetic mechanism -developmental encephalopathies.

Language: Английский

Citations

1
Coevolution with toxic prey produces functional trade-offs in sodium channels of predatory snakes DOI Open Access
Robert E. del Carlo, Jessica S. Reimche, Haley A. Moniz

et al.

Published: Feb. 8, 2024

Seemingly unrelated traits often share the same underlying molecular mechanisms, potentially generating a pleiotropic relationship whereby selection shaping one trait can simultaneously compromise another. While such functional trade-offs are expected to influence evolutionary outcomes, their actual relevance in nature is masked by obscure links between genotype, phenotype, and fitness. Here, we describe that likely govern key adaptation coevolutionary dynamics predator-prey system. Several garter snake ( Thamnophis spp.) populations have evolved resistance tetrodotoxin (TTX), potent chemical defense prey, toxic newts Taricha spp.). Snakes achieve TTX through mutations occurring at toxin-binding sites pore of skeletal muscle voltage-gated sodium channels (Na V 1.4). We hypothesized these impair basic Na functions, producing should ultimately scale up compromised organismal performance. investigate biophysical costs two species with unique independently confer resistance. show electrophysiological evidence encoded toxin-resistant alleles functionally compromised. Furthermore, muscles from snakes genotypes exhibit reduced mechanical Lastly, modeling stability channel variants partially explains impairments. Ultimately, adaptive genetic changes favoring toxin appear negatively impact function, strength, These cellular organ levels underpin locomotor deficits observed resistant may explain variation population-level success across landscape, trajectory snake-newt coevolution.

Language: Английский

Citations

1
Coevolution with toxic prey produces functional trade-offs in sodium channels of predatory snakes DOI Open Access
Robert E. del Carlo, Jessica S. Reimche, Haley A. Moniz

et al.

Published: Feb. 8, 2024

Seemingly unrelated traits often share the same underlying molecular mechanisms, potentially generating a pleiotropic relationship whereby selection shaping one trait can simultaneously compromise another. While such functional trade-offs are expected to influence evolutionary outcomes, their actual relevance in nature is masked by obscure links between genotype, phenotype, and fitness. Here, we describe that likely govern key adaptation coevolutionary dynamics predator-prey system. Several garter snake ( Thamnophis spp.) populations have evolved resistance tetrodotoxin (TTX), potent chemical defense prey, toxic newts Taricha spp.). Snakes achieve TTX through mutations occurring at toxin-binding sites pore of skeletal muscle voltage-gated sodium channels (Na V 1.4). We hypothesized these impair basic Na functions, producing should ultimately scale up compromised organismal performance. investigate biophysical costs two species with unique independently confer resistance. show electrophysiological evidence encoded toxin-resistant alleles functionally compromised. Furthermore, muscles from snakes genotypes exhibit reduced mechanical Lastly, modeling stability channel variants partially explains impairments. Ultimately, adaptive genetic changes favoring toxin appear negatively impact function, strength, These cellular organ levels underpin locomotor deficits observed resistant may explain variation population-level success across landscape, trajectory snake-newt coevolution.

Language: Английский

Citations

1
A claudin5-binding peptide enhances the permeability of the blood-brain-barrier DOI Open Access

Martina Trevisani,

Alessandro Berselli, Giulio Alberini

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 30, 2024

ABSTRACT The blood-brain barrier (BBB) is essential to maintain brain homeostasis and healthy conditions but it also prevents drugs from reaching cells. In the BBB, tight junctions (TJs) are multi-protein complexes located at interface between adjacent endothelial cells that regulate paracellular diffusion claudin-5 (CLDN5) major component of TJ portfolio, playing a pivotal role in restricting traffic. view obtaining fine control over transport across use competing peptides able bind CLDN5 induce transient regulated permeabilization passage emerging as potentially translatable strategy for clinical applications. this work, we designed tested short with improved solubility biocompatibility using combined approach involved structural modeling techniques vitro validation, generating robust workflow design, screening, optimization modulation BBB permeability. We selection 11- 16-mer compounds derived first extracellular domain CLDN5-binding Clostridium perfringens enterotoxin determined their efficiency enhancing computational analysis classified all based on affinity CLDN5, provided atom-level details binding process. From our identified novel CLDN5-derived peptide, here called f1-C5C2 , which demonstrated good biological media, efficient subunits, capability increase permeability low concentrations. peptidomimetic silico/in described can achieve reversible potential applications pharmacological treatment diseases. HIGHLIGHTS Water-soluble peptidomimetics used competitively junction proteins barrier; Trans-endothelial electrical resistance dissociation constant measurements demonstrate peptide claudin-5; Unbinding free energy calculations correlated experimental results information protein-peptide interface. Incubation allows 4K, not 70K, dextran. GRAPHICAL

Language: Английский

Citations

1