scholarly journals Mutant cycle analysis with modified saxitoxins reveals specific interactions critical to attaining high-affinity inhibition of hNaV1.7

2016 ◽  
Vol 113 (21) ◽  
pp. 5856-5861 ◽  
Author(s):  
Rhiannon Thomas-Tran ◽  
J. Du Bois
Keyword(s):  
Pain Perception ◽  
Large Body ◽  
Channel Structure ◽  
Binding Model ◽  
Voltage Gated Sodium Channels ◽  
Outer Vestibule ◽  
Selective Agents ◽  
3D Architecture ◽  
Toxin Receptor ◽  
Sar Study

Improper function of voltage-gated sodium channels (NaVs), obligatory membrane proteins for bioelectrical signaling, has been linked to a number of human pathologies. Small-molecule agents that target NaVs hold considerable promise for treatment of chronic disease. Absent a comprehensive understanding of channel structure, the challenge of designing selective agents to modulate the activity of NaV subtypes is formidable. We have endeavored to gain insight into the 3D architecture of the outer vestibule of NaV through a systematic structure–activity relationship (SAR) study involving the bis-guanidinium toxin saxitoxin (STX), modified saxitoxins, and protein mutagenesis. Mutant cycle analysis has led to the identification of an acetylated variant of STX with unprecedented, low-nanomolar affinity for human NaV1.7 (hNaV1.7), a channel subtype that has been implicated in pain perception. A revised toxin-receptor binding model is presented, which is consistent with the large body of SAR data that we have obtained. This new model is expected to facilitate subsequent efforts to design isoform-selective NaV inhibitors.

scholarly journals Oxytocin and positive couple interaction affect the perception of wound pain in everyday life

2020 ◽  
Vol 16 ◽  
pp. 174480692091869
Author(s):  
Ann-Christin Pfeifer ◽  
Paul Schroeder-Pfeifer ◽  
Ekaterina Schneider ◽  
Maren Schick ◽  
Markus Heinrichs ◽  
...  
Keyword(s):  
Social Interaction ◽  
Everyday Life ◽  
Hierarchical Linear Modeling ◽  
Pain Perception ◽  
Large Body ◽  
Controlled Study ◽  
Positive Interaction ◽  
Couple Interaction ◽  
Specific Effects ◽  
Positive Social Interaction

A large body of animal and human laboratory research has linked social interaction and support to pain perception, with a possible role for the neuropeptide oxytocin as a neuroendocrine mediator. However so far, it has been unclear whether these effects translate to ecologically valid everyday life behavior and pain perception. In a randomized placebo-controlled study, a standard suction blister skin wound was induced to N = 80 romantic couples (N = 160 individuals). Couples then received intranasal oxytocin or placebo twice daily and were either instructed to perform a positive social interaction (partner appraisal task, PAT) once in the laboratory and two times during the following five days, or not. During these days, all participants reported their subjective pain levels multiple times a day using ecologically momentary assessment. Results from hierarchical linear modeling suggest that pain levels within the couples were inter-related. In men, but not in women, oxytocin reduced pain levels. Women reported lower pain levels in the group of positive social interaction, while this effect did not show in men. These results suggest that intranasal oxytocin might have sex-specific effects with pain reducing effects in men but the opposite effects in women. In contrast, especially women benefit from positive interaction in terms of dampened pain levels after positive interaction. The results add to the evidence for health-beneficial effects of positive couple interaction and point to underlying neuroendocrine mechanisms in everyday life pain specifically. The sex-specific effects, in particular, may have implications for psychopharmacological treatment of pain in men and women.

scholarly journals Mapping the β-Scorpion Toxin Receptor Site on Voltage-Gated Sodium Channels

2010 ◽  
Vol 98 (3) ◽  
pp. 108a-109a
Author(s):  
Zhongli Zhang ◽  
Izhar Karbat ◽  
Lior Cohen ◽  
Todd Scheuer ◽  
Dalia Gordon ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Receptor Site ◽  
Scorpion Toxin ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Toxin Receptor

Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia

2018 ◽  
Vol 126 (10) ◽  
pp. 632-639
Author(s):  
Ao Ri-Ge-le ◽  
Zhuang-Li Guo ◽  
Qi Wang ◽  
Bao-Jian Zhang ◽  
Da-Wei Kong ◽  
...  
Keyword(s):  
Diabetic Neuropathy ◽  
Dorsal Root ◽  
Pain Perception ◽  
Salvia Miltiorrhiza ◽  
Thermal Hyperalgesia ◽  
Diabetic Rats ◽  
Tanshinone Iia ◽  
Painful Diabetic Neuropathy ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

AbstractPainful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models. Intraperitoneal injection (i.p.) of TIIA for 3 weeks in PDN rats significantly improved mechanical allodynia and thermal hyperalgesia. Patch clamp recordings showed that the excitability of dorsal root ganglion (DRG) nociceptive neuron was increased in diabetic state, and TIIA treatment effectively recovered the subnormality, which was achieved by preventing augments of both Tetrodotoxin-sensitive (TTX-resistant) and Tetrodotoxin-sensitive (TTX-S) sodium currents. Further, the protein expressions of voltage-gated sodium channels (VGSCs) α-subunits Nav1.3, Nav1.7 and Nav1.9 increased in DRG of diabetic rats and were normalized by TIIA application. In conclusion, this study provides evidence that the TIIA attenuated PDN by effecting VGSCs activities and expressions, indicating that the TIIA could be a promising agent for PDN treatment.

scholarly journals µ-Conotoxins Modulating Sodium Currents in Pain Perception and Transmission

2017 ◽  
Author(s):  
Elisabetta Tosti ◽  
Raffaele Boni ◽  
Alessandra Gallo
Keyword(s):  
Sodium Channels ◽  
Pain Perception ◽  
Neuronal Excitability ◽  
Current Knowledge ◽  
Disulfide Bridges ◽  
Post Translational Modifications ◽  
Active Peptides ◽  
Voltage Gated ◽  
Common Structure ◽  
Voltage Gated Sodium Channels

The Conus genus includes around 500 species of marine mollusks with a peculiar production of venomous peptides known as conotoxins (CTX). Each species is able to produce up to 200 different biological active peptides. Common structure of CTX is the low number of aminoacids stabilized by disulfide bridges and post-translational modifications that give rise to different isoforms. µ and µ-O CTX are two isoforms that specifically target voltage-gated sodium channels. These, by inducing the entrance of sodium ions in the cell, modulate the neuronal excitability by depolarizing plasma membrane and propagating the action potential. Hyperxcitability and mutations of sodium channels are responsible for perception and transmission of inflammatory and neuropathic pain states. In this review, we describe the current knowledge of µ-CTX interacting with the different sodium channels subtypes, the mechanism of action and their potential therapeutic use as analgesic compounds in the clinical management of pain conditions.

scholarly journals The Perception and Endogenous Modulation of Pain

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-25 ◽  
Author(s):  
Michael H. Ossipov
Keyword(s):  
Pain Perception ◽  
Survival Function ◽  
Pain Matrix ◽  
Voltage Gated Sodium Channels ◽  
Congenital Insensitivity ◽  
Trka Receptors ◽  
Genomic Studies ◽  
Congenital Insensitivity To Pain ◽  
Subcortical Regions ◽  
As Stress

Pain is often perceived an unpleasant experience that includes sensory and emotional/motivational responses. Accordingly, pain serves as a powerful teaching signal enabling an organism to avoid injury, and is critical to survival. However, maladaptive pain, such as neuropathic or idiopathic pain, serves no survival function. Genomic studies of individuals with congenital insensitivity to pain or paroxysmal pain syndromes considerable increased our understanding of the function of peripheral nociceptors, and especially of the roles of voltage-gated sodium channels and of nerve growth factor (NGF)/TrkA receptors in nociceptive transduction and transmission. Brain imaging studies revealed a “pain matrix,” consisting of cortical and subcortical regions that respond to noxious inputs and can positively or negatively modulate pain through activation of descending pain modulatory systems. Projections from the periaqueductal grey (PAG) and the rostroventromedial medulla (RVM) to the trigeminal and spinal dorsal horns can inhibit or promote further nociceptive inputs. The “pain matrix” can explain such varied phenomena as stress-induced analgesia, placebo effect and the role of expectation on pain perception. Disruptions in these systems may account for the existence idiopathic pan states such as fibromyalgia. Increased understanding of pain modulatory systems will lead to development of more effective therapeutics for chronic pain.

scholarly journals The Outer Vestibule of the Na+ Channel–Toxin Receptor and Modulator of Permeation as Well as Gating

Marine Drugs ◽  
2010 ◽  
Vol 8 (4) ◽  
pp. 1373-1393 ◽  
Author(s):  
René Cervenka ◽  
Touran Zarrabi ◽  
Peter Lukacs ◽  
Hannes Todt
Keyword(s):  
Na Channel ◽  
Outer Vestibule ◽  
Toxin Receptor

scholarly journals Non-extensitivity and criticality of atomic hydropathicity around a voltage-gated sodium channel’s pore: a modeling study

2021 ◽  
Author(s):  
Makros N. Xenakis ◽  
Dimos Kapetis ◽  
Yang Yang ◽  
Jordi Heijman ◽  
Stephen G. Waxman ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Single Channel ◽  
Clinical Importance ◽  
System Size ◽  
Channel Structure ◽  
Global Maximum ◽  
Coupling Energy ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Closed Pore

AbstractVoltage-gated sodium channels (NavChs) are pore-forming membrane proteins that regulate the transport of sodium ions through the cell membrane. Understanding the structure and function of NavChs is of major biophysical, as well as clinical, importance given their key role in cellular pathophysiology. In this work, we provide a computational framework for modeling system-size-dependent, i.e., cumulative, atomic properties around a NavCh’s pore. We illustrate our methodologies on the bacterial NavAb channel captured in a closed-pore state where we demonstrate that the atomic environment around its pore exhibits a bi-phasic spatial organization dictated by the structural separation of the pore domains (PDs) from the voltage-sensing domains (VSDs). Accordingly, a mathematical model describing packing of atoms around NavAb’s pore is constructed that allows—under certain conservation conditions—for a power-law approximation of the cumulative hydropathic dipole field effect acting along NavAb’s pore. This verified the non-extensitivity hypothesis for the closed-pore NavAb channel and revealed a long-range hydropathic interactions law regulating atom-packing around the NavAb’s selectivity filter. Our model predicts a PDs-VSDs coupling energy of $\sim \!282.1$ ∼ 282.1 kcal/mol corresponding to a global maximum of the atom-packing energy profile. Crucially, we demonstrate for the first time how critical phenomena can emerge in a single-channel structure as a consequence of the non-extensive character of its atomic porous environment.

scholarly journals Folding similarity of the outer pore region in prokaryotic and eukaryotic sodium channels revealed by docking of conotoxins GIIIA, PIIIA, and KIIIA in a NavAb-based model of Nav1.4

2014 ◽  
Vol 144 (3) ◽  
pp. 231-244 ◽  
Author(s):  
Viacheslav S. Korkosh ◽  
Boris S. Zhorov ◽  
Denis B. Tikhonov
Keyword(s):  
Experimental Data ◽  
Sodium Channels ◽  
Rational Design ◽  
Large Body ◽  
Homology Model ◽  
Selectivity Filter ◽  
Pore Region ◽  
X Ray ◽  
Voltage Gated Sodium Channels ◽  
Outer Pore

Voltage-gated sodium channels are targets for many drugs and toxins. However, the rational design of medically relevant channel modulators is hampered by the lack of x-ray structures of eukaryotic channels. Here, we used a homology model based on the x-ray structure of the NavAb prokaryotic sodium channel together with published experimental data to analyze interactions of the μ-conotoxins GIIIA, PIIIA, and KIIIA with the Nav1.4 eukaryotic channel. Using Monte Carlo energy minimizations and published experimentally defined pairwise contacts as distance constraints, we developed a model in which specific contacts between GIIIA and Nav1.4 were readily reproduced without deformation of the channel or toxin backbones. Computed energies of specific interactions between individual residues of GIIIA and the channel correlated with experimental estimates. The predicted complexes of PIIIA and KIIIA with Nav1.4 are consistent with a large body of experimental data. In particular, a model of Nav1.4 interactions with KIIIA and tetrodotoxin (TTX) indicated that TTX can pass between Nav1.4 and channel-bound KIIIA to reach its binding site at the selectivity filter. Our models also allowed us to explain experimental data that currently lack structural interpretations. For instance, consistent with the incomplete block observed with KIIIA and some GIIIA and PIIIA mutants, our computations predict an uninterrupted pathway for sodium ions between the extracellular space and the selectivity filter if at least one of the four outer carboxylates is not bound to the toxin. We found a good correlation between computational and experimental data on complete and incomplete channel block by native and mutant toxins. Thus, our study suggests similar folding of the outer pore region in eukaryotic and prokaryotic sodium channels.

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