scholarly journals Rational development of analgesics for the treatment of chronic pain: dissecting the molecular details of the interaction between gating modifier peptide modulators and human voltage-gated sodium channels

2020 ◽  
Author(s):  
Sassan Rahnama
Keyword(s):  
Chronic Pain ◽  
Sodium Channels ◽  
Voltage Gated ◽  
Rational Development ◽  
Voltage Gated Sodium Channels ◽  
Gating Modifier

scholarly journals Purification and Characterization of JZTx-14, a Potent Antagonist of Mammalian and Prokaryotic Voltage-Gated Sodium Channels

Toxins ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 408 ◽  
Author(s):  
Jie Zhang ◽  
Dongfang Tang ◽  
Shuangyu Liu ◽  
Haoliang Hu ◽  
Songping Liang ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Resting State ◽  
Purification And Characterization ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Steady State Inactivation ◽  
Ic50 Values ◽  
Gating Modifier ◽  
Potent Antagonist

Exploring the interaction of ligands with voltage-gated sodium channels (NaVs) has advanced our understanding of their pharmacology. Herein, we report the purification and characterization of a novel non-selective mammalian and bacterial NaVs toxin, JZTx-14, from the venom of the spider Chilobrachys jingzhao. This toxin potently inhibited the peak currents of mammalian NaV1.2–1.8 channels and the bacterial NaChBac channel with low IC50 values (<1 µM), and it mainly inhibited the fast inactivation of the NaV1.9 channel. Analysis of NaV1.5/NaV1.9 chimeric channel showed that the NaV1.5 domain II S3–4 loop is involved in toxin association. Kinetics data obtained from studying toxin–NaV1.2 channel interaction showed that JZTx-14 was a gating modifier that possibly trapped the channel in resting state; however, it differed from site 4 toxin HNTx-III by irreversibly blocking NaV currents and showing state-independent binding with the channel. JZTx-14 might stably bind to a conserved toxin pocket deep within the NaV1.2–1.8 domain II voltage sensor regardless of channel conformation change, and its effect on NaVs requires the toxin to trap the S3–4 loop in its resting state. For the NaChBac channel, JZTx-14 positively shifted its conductance-voltage (G–V) and steady-state inactivation relationships. An alanine scan analysis of the NaChBac S3–4 loop revealed that the 108th phenylalanine (F108) was the key residue determining the JZTx-14–NaChBac interaction. In summary, this study provided JZTx-14 with potent but promiscuous inhibitory activity on both the ancestor bacterial NaVs and the highly evolved descendant mammalian NaVs, and it is a useful probe to understand the pharmacology of NaVs.

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 Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes

2018 ◽  
Vol 293 (23) ◽  
pp. 9041-9052 ◽  
Author(s):  
Akello J. Agwa ◽  
Steve Peigneur ◽  
Chun Yuen Chow ◽  
Nicole Lawrence ◽  
David J. Craik ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Lipid Membranes ◽  
Spider Venom ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Modifier

scholarly journals Structural basis for the modulation of voltage-gated sodium channels by animal toxins

Science ◽  
2018 ◽  
Vol 362 (6412) ◽  
pp. eaau2596 ◽  
Author(s):  
Huaizong Shen ◽  
Zhangqiang Li ◽  
Yan Jiang ◽  
Xiaojing Pan ◽  
Jianping Wu ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Structural Basis ◽  
Shellfish Poisoning ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Puffer Fish ◽  
Gating Modifier ◽  
Extracellular Side ◽  
Fish And Shellfish ◽  
Shed Light

Animal toxins that modulate the activity of voltage-gated sodium (Nav) channels are broadly divided into two categories—pore blockers and gating modifiers. The pore blockers tetrodotoxin (TTX) and saxitoxin (STX) are responsible for puffer fish and shellfish poisoning in humans, respectively. Here, we present structures of the insect Navchannel NavPaS bound to a gating modifier toxin Dc1a at 2.8 angstrom-resolution and in the presence of TTX or STX at 2.6-Å and 3.2-Å resolution, respectively. Dc1a inserts into the cleft between VSDIIand the pore of NavPaS, making key contacts with both domains. The structures with bound TTX or STX reveal the molecular details for the specific blockade of Na+access to the selectivity filter from the extracellular side by these guanidinium toxins. The structures shed light on structure-based development of Navchannel drugs.

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.

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

scholarly journals Propofol is a Potent Gating Modifier of Voltage-Gated Sodium Channels

2017 ◽  
Vol 112 (3) ◽  
pp. 105a-106a
Author(s):  
Elaine Yang ◽  
Daniele Granata ◽  
Roderic Eckenhoff ◽  
Vincenzo Carnevale ◽  
Manuel Covarrubias
Keyword(s):  
Sodium Channels ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Modifier
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