Organic Toxins as Tools to Understand Ion Channel Mechanisms and Structure

Abstract

Ion channels constitute a varied class of membrane proteins with pivotal roles in cellular physiology and that are fundamental for neuronal signaling, hormone secretion and muscle contractility. Hence, it is not unanticipated that toxins from diverse organisms have evolved to modulate the activity of ion channels. For instance, animals such as cone snails, scorpions, spiders and snakes use toxins to immobilize and capture their prey by affecting ion channel function. This is a beautiful example of an evolutionary process that has led to the development of an injection apparatus from predators and to the existence of toxins with high affinity and specificity for a given target. Toxins have been used in the field of ion channel biophysics for several decades to gain insight into the gating mechanisms and the structure of ion channels. Through the use of these peptides, much has been learned about the ion conduction pathways, voltage-sensing mechanisms, pore sizes, kinetics, inactivation processes, etc. This review examines an assortment of toxins that have been used to study different ion channels and describes some key findings about the structure-function relationships in these proteins through the details of the toxin-ion channel interactions.

Hydration Mimicry by Membrane Ion Channels

“…In beneficial cases, drugs that block specific channels hold promise for treating neurological disorders, autoimmune diseases, and cancers (2,3,4). Peptide toxins from several poisonous animals provide examples of the detrimental possibilities (5,6). Indeed, simple divalent metal ions can be potent channel blockers, and both monovalent and divalent ions permeate selectively.…”

The Molecular Basis of Toxins’ Interactions with Intracellular Signaling via Discrete Portals

“…Ion channels are important portals for a variety of toxins interacting with the plasma membrane [60]. Under normal conditions, the physiological role of these channels is to regulate with high selectivity, the transfer of cations or anions in order to maintain a resting membrane potential and to control action potentials in excitable tissues.…”

Small Scaffolds, Big Potential: Developing Miniature Proteins as Therapeutic Agents

“…The predominant biological function of these toxins and their derivatives is to inhibit voltage‐gated ion channels on the surface of neurons. This inherent ability that has led to their use to study nerve cell conductance (Gilchrist et al, ; Morales‐Lazaro et al, ). Furthermore, this mechanism of action has led to the development of such toxins as potential therapeutics in treating cancer and cardiovascular disease (Ding et al, ; Bhavya et al, ).…”

“…Invertebrate venoms contain small proteins that function to inhibit voltage‐gated ion channels (Gilchrist et al, ). Many of these toxic substances have been used as probes to study cell physiology and have revealed a host of information about ion channel structure/function relationships (Morales‐Lazaro et al, ). As scaffolds, such proteins offer a unique platform from which to design potential therapeutics because their folds are often stabilized by disulfide linkages, allowing the proteins to retain their native folds even with major changes to the amino acid sequence (Vita et al, ).…”