Ion channel toxins and therapeutics: from cone snail venoms to ciguatera.
Ion channels are intimately linked to all neurotransmission and neurotransmitter release processes, but in disease states often contribute adversely to disease pathology. The diversity and distribution of ion channel types and subtypes being uncovered through the use of molecular biology and toxin probes present an exciting opportunity for the discovery of new, more selective drugs. Among ion channels targeted by cone shell venom peptides (conotoxins) are the voltage-sensitive sodium, calcium, and potassium channels which open and then close (inactivate) in response to membrane depolarization, and thus regulate neurotransmission and the neurotransmitter release process. Conotoxins also target ligand-gated ion channels, including the NMDA-glutamate channel and the nicotinic acetylcholine receptor channel. The diversity of subtypes, especially those subtypes upregulated in disease states, makes ion channels a rapidly expanding therapeutic area. Conotoxins represent some of the most selective inhibitors of ion channel subtypes and have often been used as the defining ligand. In this overview, the structures and therapeutic potential of conotoxins active at ion channels are highlighted. The activity and structures are then contrasted with ciguatoxins, which are responsible for the food poisoning known as ciguatera. A universal liquid chromatography/mass spectrometry approach to the detection of these classes of toxins is briefly discussed.