scholarly journals Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes

2015 ◽  
Vol 6 ◽  
Author(s):  
Cedric J. Laedermann ◽  
Hugues Abriel ◽  
Isabelle Decosterd
Keyword(s):  
Chronic Pain ◽  
Sodium Channels ◽  
Post Translational Modifications ◽  
Voltage Gated ◽  
Pain Syndromes ◽  
Voltage Gated Sodium Channels ◽  
Chronic Pain Syndromes

scholarly journals Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 626 ◽  
Author(s):  
Yashad Dongol ◽  
Fernanda Caldas Cardoso ◽  
Richard J Lewis
Keyword(s):  
Chronic Pain ◽  
Sodium Channels ◽  
Structural Features ◽  
Voltage Gated ◽  
Subtype Selectivity ◽  
Voltage Gated Sodium Channels ◽  
Neuronal Signalling ◽  
Pain Pathways ◽  
Nav Channels ◽  
Chronic Pain Conditions

Voltage-gated sodium channels (NaVs) are a key determinant of neuronal signalling. Neurotoxins from diverse taxa that selectively activate or inhibit NaV channels have helped unravel the role of NaV channels in diseases, including chronic pain. Spider venoms contain the most diverse array of inhibitor cystine knot (ICK) toxins (knottins). This review provides an overview on how spider knottins modulate NaV channels and describes the structural features and molecular determinants that influence their affinity and subtype selectivity. Genetic and functional evidence support a major involvement of NaV subtypes in various chronic pain conditions. The exquisite inhibitory properties of spider knottins over key NaV subtypes make them the best lead molecules for the development of novel analgesics to treat chronic pain.

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 Role of Voltage-Gated Sodium Channels in Pain Signaling

2019 ◽  
Vol 99 (2) ◽  
pp. 1079-1151 ◽  
Author(s):  
David L. Bennett ◽  
Alex J. Clark ◽  
Jianying Huang ◽  
Stephen G. Waxman ◽  
Sulayman D. Dib-Hajj
Keyword(s):  
Chronic Pain ◽  
Sodium Channels ◽  
Sensory Neuron ◽  
Sensory Neurons ◽  
Expression Patterns ◽  
Sensory Transduction ◽  
Gene Variants ◽  
Sensory Stimuli ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

Acute pain signaling has a key protective role and is highly evolutionarily conserved. Chronic pain, however, is maladaptive, occurring as a consequence of injury and disease, and is associated with sensitization of the somatosensory nervous system. Primary sensory neurons are involved in both of these processes, and the recent advances in understanding sensory transduction and human genetics are the focus of this review. Voltage-gated sodium channels (VGSCs) are important determinants of sensory neuron excitability: they are essential for the initial transduction of sensory stimuli, the electrogenesis of the action potential, and neurotransmitter release from sensory neuron terminals. Nav1.1, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 are all expressed by adult sensory neurons. The biophysical characteristics of these channels, as well as their unique expression patterns within subtypes of sensory neurons, define their functional role in pain signaling. Changes in the expression of VGSCs, as well as posttranslational modifications, contribute to the sensitization of sensory neurons in chronic pain states. Furthermore, gene variants in Nav1.7, Nav1.8, and Nav1.9 have now been linked to human Mendelian pain disorders and more recently to common pain disorders such as small-fiber neuropathy. Chronic pain affects one in five of the general population. Given the poor efficacy of current analgesics, the selective expression of particular VGSCs in sensory neurons makes these attractive targets for drug discovery. The increasing availability of gene sequencing, combined with structural modeling and electrophysiological analysis of gene variants, also provides the opportunity to better target existing therapies in a personalized manner.

Sodium Channels in Human Pain Disorders: Genetics and Pharmacogenomics

2019 ◽  
Vol 42 (1) ◽  
pp. 87-106 ◽  
Author(s):  
Sulayman D. Dib-Hajj ◽  
Stephen G. Waxman
Keyword(s):  
Chronic Pain ◽  
Sodium Channels ◽  
Molecular Genetic ◽  
Channel Blockers ◽  
Peripheral Neurons ◽  
Global Challenge ◽  
Pain Syndromes ◽  
Voltage Gated Sodium Channels ◽  
Peripheral Pain ◽  
Recent Developments

Acute pain is adaptive, but chronic pain is a global challenge. Many chronic pain syndromes are peripheral in origin and reflect hyperactivity of peripheral pain-signaling neurons. Current treatments are ineffective or only partially effective and in some cases can be addictive, underscoring the need for better therapies. Molecular genetic studies have now linked multiple human pain disorders to voltage-gated sodium channels, including disorders characterized by insensitivity or reduced sensitivity to pain and others characterized by exaggerated pain in response to normally innocuous stimuli. Here, we review recent developments that have enhanced our understanding of pathophysiological mechanisms in human pain and advances in targeting sodium channels in peripheral neurons for the treatment of pain using novel and existing sodium channel blockers.

scholarly journals Voltage gated sodium channels as therapeutic targets for chronic pain

2019 ◽  
Vol Volume 12 ◽  
pp. 2709-2722 ◽  
Author(s):  
Renee Siu Yu Ma ◽  
Kayani Kayani ◽  
Danniella Whyte Oshodi ◽  
Aiyesha Whyte Oshodi ◽  
Nitish Nachiappan ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sodium Channels ◽  
Therapeutic Targets ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels
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