Toxins That Affect Voltage-Gated Sodium Channels

Abstract

Voltage-gated sodium channels (VGSCs) are critical in generation and conduction of electrical signals in multiple excitable tissues. Natural toxins, produced by animal, plant, and microorganisms, target VGSCs through diverse strategies developed over millions of years of evolutions. Studying of the diverse interaction between VGSC and VGSC-targeting toxins has been contributing to the increasing understanding of molecular structure and function, pharmacology, and drug development potential of VGSCs. This chapter aims to summarize some of the current views on the VGSC-toxin interaction based on the established receptor sites of VGSC for natural toxins.

Enantioselective Total Syntheses of Grayanane Diterpenoids: (−)-Grayanotoxin III, (+)-Principinol E, and (−)-Rhodomollein XX

“…Responsible for generating action potentials in neurons and cardiac and skeletal muscle cells, voltage-gated sodium channels (VGSCs) have been associated with a number of inherited and acquired diseases, and hence serving as promising targets for drug discovery . Natural toxins targeting the central cavity of the ion permeation pathway of VGSCs (site II) are useful tools given their unique properties . Recent advances of synthetic chemistry have shed new light on not only their structure–activity relationship but also intriguing problems of channel dynamics .…”

Heterologous functional expression of ascidian Nav1 channels and close relationship with the evolutionary ancestor of vertebrate Nav channels

“…Ascidians are filter feeders and feed on planktonic algae and microbes. Many Nav1 targeting toxins including TTX are produced by algae and microbes in oceans ( 49 ). It is possible that TTX insensitivity in ascidians or perhaps in other related species reflects an adaption necessary to their lifestyle as marine filter feeders.…”

Venom-derived pain-causing toxins: insights into sensory neuron function and pain mechanisms

“…The pharmacology of these plant toxins has been extensively discussed elsewhere, and in the interest of a focus on venom-derived molecules, the reader is referred to other reviews on the topic. 61,83 Besides small molecule irritants and allergens, some plants also produce bona fide venoms. In stinging nettles, a complex, pain-producing fluid-by the above definition a "venom"-is injected by stinging hairs called trichomes, which act as small hypodermic syringes.…”

“…The pharmacology of these plant toxins has been extensively discussed elsewhere, and in the interest of a focus on venom-derived molecules, the reader is referred to other reviews on the topic. 61,83…”