Abstract:The voltage-gated sodium (Nav) channel is a target for a number of drugs, insecticides and neurotoxins. These bind to at least seven identified neurotoxin binding sites and either block conductance or modulate sodium channel gating and / or kinetics. A number of polypeptide toxins from the venoms of araneomorph and mygalomorph spiders have been isolated and characterized that interact with several of these sites. Certain huwentoxins and hainantoxins appear to target site 1 to block Nav channel conductance. The… Show more
Abstract:Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na + -dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera.
Abstract:Ciguatoxins are cyclic polyether toxins, derived from marine dinoflagellates, which are responsible for the symptoms of ciguatera poisoning. Ingestion of tropical and subtropical fin fish contaminated by ciguatoxins results in an illness characterised by neurological, cardiovascular and gastrointestinal disorders. The pharmacology of ciguatoxins is characterised by their ability to cause persistent activation of voltage-gated sodium channels, to increase neuronal excitability and neurotransmitter release, to impair synaptic vesicle recycling, and to cause cell swelling. It is these effects, in combination with an action to block voltage-gated potassium channels at high doses, which are believed to underlie the complex of symptoms associated with ciguatera. This review examines the sources, structures and pharmacology of ciguatoxins. In particular, attention is placed on their cellular modes of actions to modulate voltage-gated ion channels and other Na + -dependent mechanisms in numerous cell types and to current approaches for detection and treatment of ciguatera.
“…Moreover, even though the vast majority of spiders prey primarily on invertebrates, there is no evolutionary selection pressure to prevent spider toxins acting on vertebrate ion channels. It is therefore not surprising that many spider-venom peptides have been found to modulate the activity of vertebrate Na V channels 33,70,83 . rings of amino acid residues that form the ion-selectivity filter and constitute the proposed neurotoxin receptor site 1 for the water-soluble guanidinium toxins TTX and saxitoxin.…”
Section: Spider Venom Peptides As Na V -Targeted Analgesic Drugsmentioning
confidence: 99%
“…Indeed, four of the seven pharmacological sites on vertebrate Na V channels are defined by the binding of mollusk or arachnid toxins. Na V channel modulation is one of the major pharmacologies of spider venoms 69,70 and the spider toxins responsible have proved to be valuable tools for understanding the structure and function of Na V channels 33,71 .…”
Section: Spider Venom Peptides As Na V -Targeted Analgesic Drugsmentioning
Chronic pain is responsible for great physical, mental and economic loss. While there are diverse methods available for managing pain, such as NSAID, opioids and local anesthetics, common issues associated such as addiction and tolerance highlights the unmet demand for a novel analgesic aimed at a novel target.Numerous reports on individuals suffering from loss of function mutations in SCN9A marker, which leads to complete inability to feel pain, yet otherwise normal physiology, has led to the recognition of voltage gated sodium channel 1.7 (Na V 1.7) as a prime pain target.Other reports of gain of function mutations that lead to conditions such as paroxysmal extreme pain disorder and primary erythromelalgia confirms the validity of this target.However the presence of nine closely related subtypes of voltage gated sodium channels, Na V 1.1-Na V 1.9 introduces complications as any cross inhibition may lead to detrimental results. For example inhibition of Na V 1.5 subtype could result in cardiac arrhythmia to complete cardiac arrest and death. Therefor it is of utmost importance that any pharmaceutical agent used to inhibit Na V 1.7 is highly specific for Na V 1.7 and display no cross reactivity on other voltage gated channels.Spiders are one of the most successful terrestrial predators; their venoms have evolved over many millions of years to selectively and potently inhibit nervous system targets in order to rapidly paralyze their prey. Spider-venom peptidomes have been identified as one of the largest known libraries of compounds with very high potency and specificity towards nervous system targets.Spider toxins listed in the Arachnoserver database have been classified into 12 families of sodium channel toxins (NaSpTx), denoted NaSpTx Families 1-12, based on the level of sequence conservation and intercystine spacing. NaSpTx family 2 is the largest toxin family; it comprises 34 peptides of theraphosid origin.This thesis primarily aims at discovering novel inhibitors of Na V 1.7. However the intriguing fact that people suffering form congenital indifference to pain also suffers form anosmia, has lead to efforts of understanding the role of Na V 1.7 in olfaction. This study has been iii completed with the finding that Na V 1.7 is located along axons of olfactory neurones. These findings have been published and research article is attached as chapter 4.During the initial discovery phase of this project, an assay guided fractionation method was used to identify Na V 1.7 inhibitors form six spider venoms. This resulted in nine fully sequenced peptides where four of these belonged to NaSpTx family 2. This included the well-known β/ω-TRTX-Tp1a (Protoxin1). Three novel peptides discovered were named β-TRTX-Pe1a, µ-TRTX-Pe1b, and U-TRTX-Pa1a.A complete alanine scan of β/ω-TRTX-Tp1a on Na V 1.7 was conducted using a Xenopus laevis oocyte based tethered toxin method. Residues that were important for Na V 1.7 binding were mapped onto the three-dimensional structure of β/ω-TRTX-Tp1a. Three novel toxin peptides β-TR...
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