Guanidinium Toxins and Their Interactions with Voltage-Gated Sodium Ion Channels

Abstract

Guanidinium toxins, such as saxitoxin (STX), tetrodotoxin (TTX) and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and ion flux blockage capacity for voltage-gated sodium channels (NaV). Members of the STX group, known collectively as paralytic shellfish toxins (PSTs), are produced among three genera of marine dinoflagellates and about a dozen genera of primarily freshwater or brackish water cyanobacteria. In contrast, toxins of the TTX group occur mainly in macrozoa, particularly among puffer fish, several species of marine invertebrates and a few terrestrial amphibians. In the case of TTX and analogs, most evidence suggests that symbiotic bacteria are the origin of the toxins, although endogenous biosynthesis independent from bacteria has not been excluded. The evolutionary origin of the biosynthetic genes for STX and analogs in dinoflagellates and cyanobacteria remains elusive. These highly potent molecules have been the subject of intensive research since the latter half of the past century; first to study the mode of action of their toxigenicity, and later as tools to characterize the role and structure of NaV channels, and finally as therapeutics. Their pharmacological activities have provided encouragement for their use as therapeutants for ion channel-related pathologies, such as pain control. The functional role in aquatic and terrestrial ecosystems for both groups of toxins is unproven, although plausible mechanisms of ion channel regulation and chemical defense are often invoked. Molecular approaches and the development of improved detection methods will yield deeper understanding of their physiological and ecological roles. This knowledge will facilitate their further biotechnological exploitation and point the way towards development of pharmaceuticals and therapeutic applications.

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

“…Puffer fish poisoning, resulting from consumption of TTXcontaining fish, was documented thousands of years ago in China and Egypt and later in Japan and Mexico (13,14). TTX was subsequently shown to be present in venom of the deadly blue-ringed octopus, in the poisonous secre-tions of frogs and newts, and in predatory moon snails; these animals do not synthesize TTX but rather acquire it from endosymbiotic bacteria (15). It was discovered in the mid-20th century that the potent toxicity of TTX is due to suppression of action potential generation through specific inhibition of Na + influx (14,(16)(17)(18).…”

Natural Voltage‐Gated Sodium Channel Ligands: Biosynthesis and Biology

“…It is unknown if these frogs still produce zetekitoxins in captivity. As 3 has only been found to be produced by microorganisms and not by complex higher organisms, it is very likely that zetekitoxins are also derived from microbial sources on the skin. Evidence of cyanobacteria, the same class of organisms known to produce 3 , have been identified on the skin of both wild and captive populations of A. zeteki .…”

“…Although Panamaniang olden frogs are functionally extinct in the wild, severalz oos have developede xceptional programs in efforts to repopulate the species in captivity,i ncluding the San Diego, Detroit, and SmithsonianN ational Zoos. It is unknowni ft hese frogs still produce zetekitoxins in captivity.A s3 has only been found to be produced by microorganisms and not by complex highero rganisms, [35] it is very likely that zeteki- toxins are also derived from microbial sources on the skin. Evidence of cyanobacteria, the same class of organisms knownt o produce 3,h ave been identified on the skin of both wild and captive populations of A. zeteki.…”

Enzymes that detoxify marine toxins

“…Signs of cellular crisis are sometimes produced in the absence of an infection, so mechanisms are needed to prevent the proteins from trigger ing an inappropriate inflammatory response. Sharif et al 1 report a structural study on page 338 that investigates an immunesensor protein called NLRP3, revealing that a protein called NEK7 acts as a 'licence' that enables this protein to cause inflammation.…”

“…The difficulties of accessing structural analogues have hampered efforts to inves tigate a family of natural products called paralytic shellfish toxins (PSTs) as candidate therapeutics for pain 1 . Many PSTs are highly potent (they elicit a strong response from their molecular biological targets) and are therefore highly toxic, which has hindered their devel opment as drugs and has generated interest in accessing less potent analogues.…”