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.
Highlights
These studies indicated that the functional Kv1 channel is a large (Mr ~400 kDa) sialoglycoprotein complex consisting of four pore-forming α-subunits and four cytoplasmically associated auxiliary β-proteins [28] that modulate K+ channel activation and inactivation kinetics
Since κJ conotoxin pl14a is broader in selectivity among Kv1 channels expressed in dorsal root ganglion (DRG), CceIXa might be more selective for particular combinations of heteromeric Kv1 channels
Other Kv type 1 sea anemone toxins are known to interact with Kv1 channels; little follow has been completed looking at their selectivity or therapeutic potential in depth
Summary
Voltage-gated K+ channels (Kv) are intrinsic plasma membrane proteins mediating the selective flow of K+ ions down their electrochemical gradient in response to a depolarization in the transmembrane electric field [1]. Voltage-gated ionand channels can inactivate from the inactivation processes have molecular been thoroughly examined functionally structurally, identifying pre-openinactivation closed-states The first Kv1 complexes were purified from mammalian brain using the snake venom toxins called dendrotoxins (DTX) These studies indicated that the functional Kv1 channel is a large (Mr ~400 kDa) sialoglycoprotein complex consisting of four pore-forming α-subunits and four cytoplasmically associated auxiliary β-proteins [28] that modulate K+ channel activation and inactivation kinetics (for a thorough review, refer to Reference [29]). All Potassium Voltage-gated channel subfamily A Member gene (KCNA) transcripts encoding Kv1 α-subunits yield functional homo-tetrameric complexes with distinct biophysical and pharmacological profiles [35], (Figure 1c). The less abundant Kv1.1 subunit is consistently identified in oligomers containing Kv1.2 channels
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