scholarly journals Antagonist action of progesterone at σ-receptors in the modulation of voltage-gated sodium channels

2011 ◽  
Vol 300 (2) ◽  
pp. C328-C337 ◽  
Author(s):  
Molly Johannessen ◽  
Dominique Fontanilla ◽  
Timur Mavlyutov ◽  
Arnold E. Ruoho ◽  
Meyer B. Jackson
Keyword(s):  
Receptor Subtypes ◽  
Receptor Ligands ◽  
Patch Clamp Recording ◽  
Membrane Action ◽  
Channel Modulation ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Wide Range ◽  
Liver Membranes ◽  
Antagonist Action

σ-Receptors are integral membrane proteins that have been implicated in a number of biological functions, many of which involve the modulation of ion channels. A wide range of synthetic ligands activate σ-receptors, but endogenous σ-receptor ligands have proven elusive. One endogenous ligand, dimethyltryptamine (DMT), has been shown to act as a σ-receptor agonist. Progesterone and other steroids bind σ-receptors, but the functional consequences of these interactions are unclear. Here we investigated progesterone binding to σ1- and σ2-receptors and evaluated its effect on σ-receptor-mediated modulation of voltage-gated Na+ channels. Progesterone binds both σ-receptor subtypes in liver membranes with comparable affinities and blocks photolabeling of both subtypes in human embryonic kidney 293 cells that stably express the human cardiac Na+ channel Nav1.5. Patch-clamp recording in this cell line tested Na+ current modulation by the σ-receptor ligands ditolylguanidine, PB28, (+)SKF10047, and DMT. Progesterone inhibited the action of these ligands to varying degrees, and some of these actions were reduced by σ1-receptor knockdown with small interfering RNA. Progesterone inhibition of channel modulation by drugs was consistent with stronger antagonism of σ2-receptors. By contrast, progesterone inhibition of channel modulation by DMT was consistent with stronger antagonism of σ1-receptors. Progesterone binding to σ-receptors blocks σ-receptor-mediated modulation of a voltage-gated ion channel, and this novel membrane action of progesterone may be relevant to changes in brain and cardiovascular function during endocrine transitions.

scholarly journals Voltage-Gated Sodium Channels: A Prominent Target of Marine Toxins

Marine Drugs ◽  
2021 ◽  
Vol 19 (10) ◽  
pp. 562
Author(s):  
Rawan Mackieh ◽  
Rita Abou-Nader ◽  
Rim Wehbe ◽  
César Mattei ◽  
Christian Legros ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Physiological Role ◽  
Supporting Cell ◽  
Cone Snail ◽  
Marine Toxins ◽  
Marine Animals ◽  
Communication Signals ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Wide Range

Voltage-gated sodium channels (VGSCs) are considered to be one of the most important ion channels given their remarkable physiological role. VGSCs constitute a family of large transmembrane proteins that allow transmission, generation, and propagation of action potentials. This occurs by conducting Na+ ions through the membrane, supporting cell excitability and communication signals in various systems. As a result, a wide range of coordination and physiological functions, from locomotion to cognition, can be accomplished. Drugs that target and alter the molecular mechanism of VGSCs’ function have highly contributed to the discovery and perception of the function and the structure of this channel. Among those drugs are various marine toxins produced by harmful microorganisms or venomous animals. These toxins have played a key role in understanding the mode of action of VGSCs and in mapping their various allosteric binding sites. Furthermore, marine toxins appear to be an emerging source of therapeutic tools that can relieve pain or treat VGSC-related human channelopathies. Several studies documented the effect of marine toxins on VGSCs as well as their pharmaceutical applications, but none of them underlined the principal marine toxins and their effect on VGSCs. Therefore, this review aims to highlight the neurotoxins produced by marine animals such as pufferfish, shellfish, sea anemone, and cone snail that are active on VGSCs and discuss their pharmaceutical values.

Voltage-gated sodium channels and pain-related disorders

2016 ◽  
Vol 130 (24) ◽  
pp. 2257-2265 ◽  
Author(s):  
Alexandros H. Kanellopoulos ◽  
Ayako Matsuyama
Keyword(s):  
Sodium Channels ◽  
Protein Complexes ◽  
Transmembrane Protein ◽  
Kinetic Properties ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Wide Range ◽  
Neuronal Types ◽  
Firing Properties

Voltage-gated sodium channels (VGSCs) are heteromeric transmembrane protein complexes. Nine homologous members, SCN1A–11A, make up the VGSC gene family. Sodium channel isoforms display a wide range of kinetic properties endowing different neuronal types with distinctly varied firing properties. Among the VGSCs isoforms, Nav1.7, Nav1.8 and Nav1.9 are preferentially expressed in the peripheral nervous system. These isoforms are known to be crucial in the conduction of nociceptive stimuli with mutations in these channels thought to be the underlying cause of a variety of heritable pain disorders. This review provides an overview of the current literature concerning the role of VGSCs in the generation of pain and heritable pain disorders.

Mechanism linking NMDA receptor activation to modulation of voltage-gated sodium current in distal retina

2003 ◽  
Vol 284 (5) ◽  
pp. C1193-C1204 ◽  
Author(s):  
Scott F. Davis ◽  
Cindy L. Linn
Keyword(s):  
Sodium Channel ◽  
Nmda Receptors ◽  
Sodium Channels ◽  
Calcium Influx ◽  
Receptor Activation ◽  
Horizontal Cells ◽  
Channel Modulation ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Nmda Channels

In this study, we investigated the mechanism that links activation of N-methyl-D-aspartate (NMDA) receptors to inhibition of voltage-gated sodium channels in isolated catfish cone horizontal cells. NMDA channels were activated in voltage-clamped cells incubated in low-calcium saline or dialyzed with the calcium chelator BAPTA to determine that calcium influx through NMDA channels is required for sodium channel modulation. To determine whether calcium influx through NMDA channels triggers calcium-induced calcium release (CICR), cells were loaded with the calcium-sensitive dye calcium green 2 and changes in relative fluorescence were measured in response to NMDA. Responses were compared with measurements obtained when caffeine depleted stores. Voltage-clamp studies demonstrated that CICR modulated sodium channels in a manner similar to that of NMDA. Blocking NMDA receptors with AP-7, blocking CICR with ruthenium red, depleting stores with caffeine, or dialyzing cells with calmodulin antagonists W-5 or peptide 290–309 all prevented sodium channel modulation. These results support the hypothesis that NMDA modulation of voltage-gated sodium channels in horizontal cells requires CICR and activation of a calmodulin-dependent signaling pathway.

scholarly journals Erratum to: Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?

2020 ◽  
Author(s):  
Zhi-mei Li ◽  
Li-xia Chen ◽  
Hua Li
Keyword(s):  
Open Access ◽  
Sodium Channels ◽  
Voltage Gated ◽  
Internet Portal ◽  
Creative Commons ◽  
Link Type ◽  
Voltage Gated Sodium Channels

The article “Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?”, written by Zhi-mei LI, Li-xia CHEN, Hua LI, was originally published electronically on the publisher’s internet portal on December 2019 without open access. With the author(s)’ decision to opt for Open Choice, the copyright of the article is changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The original article has been corrected.Corresponding authors: Li-xia CHEN, Hua LI

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