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Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds

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Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds marine drugs Review Marine Toxins Targeting Kv1 Channels: Pharmacological Tools and Therapeutic Scaffolds 1,2, 3, 3, Rocio K. Finol-Urdaneta * , Aleksandra Belovanovic y, Milica Micic-Vicovac y, Gemma K. Kinsella 4, Jeffrey R. McArthur 1 and Ahmed Al-Sabi 3,* 1 Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia; jeff[email protected] 2 Electrophysiology Facility for Cell Phenotyping and Drug Discovery, Wollongong, NSW 2522, Australia 3 College of Engineering and Technology, American University of the Middle East, Kuwait; [email protected] (A.B.); [email protected] (M.M.-V.) 4 School of Food Science and Environmental Health, College of Sciences and Health, Technological University Dublin, D07 ADY7 Dublin, Ireland; [email protected] * Correspondence: rfi[email protected] (R.K.F.-U.); [email protected] (A.A.-S.); Tel.: +965-22251400 (ext.1798) (A.A.-S.) These authors contributed equally to this review. y Received: 3 February 2020; Accepted: 16 March 2020; Published: 20 March 2020 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. Keywords: bioactives; conotoxins 2; Kv1; marine toxins; modulators; potassium channels; sea anemone toxins 1. Introduction 1.1. Kv1 Channels 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]. The selectivity and voltage dependence of Kv channels make them central players in virtually all physiological functions, including the maintenance and modulation of neuronal [2–4] and muscular (both cardiac and skeletal) excitability [5–7], regulation of calcium signalling cascades (reviewed by Reference [8]), control of cell volume [9,10], immune response [11], hormonal secretion [12], and others. The Kv channel α-subunit belongs to the six transmembrane (6-TM) family of ion channels (Figure1a,b) in which the voltage-sensing domain (VSD) formed by transmembrane segments S1–S4 Mar. Drugs 2020, 18, 173; doi:10.3390/md18030173 www.mdpi.com/journal/marinedrugs Mar.Mar. Drugs Drugs 20192020,, 1718,, x 173 FOR PEER REVIEW 22 of of 31 28 The Kv channel α-subunit belongs to the six transmembrane (6-TM) family of ion channels (Figurecontrols 1a,b) pore in opening which the via voltage-sensing the S4–S5 intracellular domain (VSD) loop thatformed is connected by transmembrane to the pore segments domain S1–S4 (PD). controlsThe PD ispore formed opening by transmembranevia the S4–S5 intracellular segments l S5–S6oop that including is connected a re-entrant to the pore pore domain loop bearing (PD). The the PDpotassium is formed selectivity by transmembrane sequence TVGYG segments [13]. S5–S6 Depolarization including a of re-entrant the transmembrane pore loop electricbearing fieldthe potassiuminduces a conformationalselectivity sequence change TVGYG in the VSD [13]. that Depola leadsrization to channel of activationthe transmembrane, leading to opening electric offield the induceswater-filled a conformational permeation pathway change permittingin the VSD Kthat+ to leads flow to down channel their activation electrochemical, leading gradient. to opening Upon of therepolarization, water-filled thepermeation VSD returns pathway to its permitting resting state, K+closing to flow the down channel their gate electrochemical and terminating gradient. ionic Uponflow inrepolarization, a process called the deactivation.VSD returns to Immediately its resting state, after deactivation,closing the channel channels gate can and be terminating reactivated; ionichowever, flow if depolarization-inducedin a process called deactivation. channel activation Immediately extends beyondafter deactivation, a few milliseconds, channels inactivation can be reactivated;ensues, ceasing however, K+ permeability. if depolarization-indu Kv channels recoverced channel from inactivation activation onlyextends after spendingbeyond enougha few milliseconds,time at a hyperpolarized inactivation potentialensues, ceasing [14]. The K+ molecular permeability underpinnings. Kv channels of recover the inactivation from inactivation processes onlyhave after been spending thoroughly enough examined time functionallyat a hyperpolar andized structurally, potential identifying[14]. The molecular various inactivationunderpinnings types of theinvolving inactivation distinct processes and complex have molecularbeen thoroughly mechanisms. examined Voltage-gated functionally ion and channels structurally, can inactivate identifying from variouspre-open inactivation closed-states types (closed-state involving inactivation, distinct and CSI) complex or from molecular the open mechanisms. state(s) (open-state Voltage-gated inactivation, ion channelsOSI) [15]. can Inactivation inactivate canfrom also pre-open be categorized closed-states depending (closed-state on the inactivation, speed of its onsetCSI) or upon from activation. the open state(s)In some (open-state Kv channels, inactivation, fast inactivation OSI) [15]. or N-type Inactivation inactivation can also occurs be sooncategorized after the depending channel activates on the speedand it isof mainlyits onset due upon to an activation. intracellular In block some by Kv the cha channel’snnels, fast intracellular inactivation N-terminus or N-type hence inactivation known as occursthe inactivation soon after particlethe channel [16]. activates This process and it has is mainly been directly due to observedan intracellular by cryo-electron block by the microscopy channel’s intracellular(cryo-EM) in N-terminus a related prokaryotic hence known K channel as the [17 ].inacti In additionvation particle to N-type [16]. inactivation, In addition a common to N-type but inactivation,relatively slower a common process but happens relatively after slower tens process or hundreds happens of after milliseconds tens or hu fromndreds channel of milliseconds activation fromthat ischannel termed activation C-type (or that slow) is termed inactivation C-type [(or18 ].slow) Even inactivation though the [17]. extent Even and though complexity the extent of slowand complexityinactivation of remain slow theinactivation subjects of remain investigation, the subjec the porets of structureinvestigation, and the the permeating pore structure ions appearand the to permeatingplay a vital roleions [ 19appear]. Recent to play structural a vital and role functional [18]. Recent studies structural support and a mechanism functional throughstudies support which the a mechanismredistribution through of structural which water the moleculesredistribution accompanies of structural the rearrangementwater molecules of amino accompanies acids within the rearrangementthe channel’s inner of amino cavity acids and outerwithin vestibule, the channel’s ultimately inner leading cavity toand the outer collapse vestibule, of the permeationultimately leadingpathway to in the C-type collapse inactivation of the permeation (reviewed pathway in Reference in C-type [20]). inactivation Modulation (reviewed of the inactivation in Reference process [19]). is Modulationa powerful strategyof the inactivation to control theprocess cellular is a availabilitypowerful strategy of Kv channel-mediated to control the cellular currents; availability thus, both of Kv N- channel-mediatedand C-type inactivation currents; are responsivethus, both N- to and the cellularC-type inactivation redox environment are responsive [21]. For to instance, the cellular structural redox environmentmotifs within [20]. the KvFor channel’s instance, N-terminusstructural motifs/inactivation within particlethe Kv servechannel’s as sensors N-terminus/inactivation of the cytoplasmic particleredox potential serve as [sensors22]. of the cytoplasmic redox potential [21]. FigureFigure 1. 1. ((aa)) Schematic Schematic illustration illustration of of K KVV channelchannel membrane membrane topology topology depicting depicting the the 6 6 transmembrane transmembrane subunitssubunits including including the the voltage voltage sensing sensing domain domain (vol (voltage-sensingtage-sensing domain domain (VSD): (VSD): S1–S4) S1–S4) and and the the pore pore domaindomain (PD) (PD) between between S5 S5 and and S6 S6 segments. segments. ( (bb)) Top Top and and side side views views of of representative representative homomeric
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