Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

Abstract

Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ’s exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.

Molecular and Functional Characterization of Neurogenin-2 Induced Human Sensory Neurons

“…Importantly, differential modulation of I K can determine the response modality of their hosting neurons (González et al, 2017). The sheer abundance and diversity of K + channels are a reflection of their relevance but also a daunting obstacle in their study at the physiological level (Cordeiro et al, 2019;Finol-Urdaneta et al, 2020;Giacobassi et al, 2020). A significant body of work on the various voltage-gated I K present in rodent DRGs exists, yet little, if anything, is known regarding the various K + conductances present in human sensory neurons.…”

“…Potassium currents (I K ) are crucial regulators of neuronal excitability and homeostasis as they contribute to the RMP and membrane repolarization, thus they modulate the shape, duration, and frequency of APs. Voltage activated K + (Kv) channels constitute the most diverse family with 40 Kv members organized in 12 subfamilies which can make physiological identification of ion channels in neurons challenging (Finol-Urdaneta et al, 2020). Yet, the properties and pharmacology of I K provide valuable information about sensory neuron functional subtypes (Giacobassi et al, 2020).…”

The Anemonia sulcata Toxin BDS-I Protects Astrocytes Exposed to Aβ1–42 Oligomers by Restoring [Ca2+]i Transients and ER Ca2+ Signaling

“…In this respect, toxins from marine organisms with a high selectivity towards ion channels [ 37 , 39 , 40 ] may provide molecular tools to treat ion channel-related diseases [ 41 ].…”

A molecular lid mechanism of K+channel blocker action revealed by a cone peptide

“…A "lid" or "turret" mode of action was first promoted based on the observation the HERG specific toxin ErgTX blocked currents through this channel despite lacking a conserved lysine, in a [K + ]o independent manner 18,32 . While the exact molecular details involved in this type of block were not described, several toxins were proposed to share this mode of action based on their biophysical and pharmacological traits [33][34][35][36][37] . The binding of KTX to the KcaA-Kv1.3 chimera was demonstrated to induce widening of the entrance region to the selectivity filter and a rotation of the D80 sidechain, both phenomena interpreted as an induced fit between the toxin and the channel proteins 38 .…”