Abstract
Ion channels play a key role in our body to regulate homeostasis and conduct electrical signals. With the help of advances in structural biology, as well as the discovery of numerous channel modulators derived from animal toxins, we are moving toward a better understanding of the function and mode of action of ion channels. Their ubiquitous tissue distribution and the physiological relevancies of their opening and closing suggest that cation channels are particularly attractive drug targets, and years of research has revealed a variety of natural toxins that bind to these channels and alter their function. In this review, we provide an introductory overview of the major cation ion channels: potassium channels, sodium channels and calcium channels, describe their venom-derived peptide modulators, and how these peptides provide great research and therapeutic value to both basic and translational medical research.
Introduction
Cone snails whose shells are coveted for their elaborate patterns, yellow dart frogs measuring just a few centimeters long, and transparent bell-shaped jellyfish with delicate tentacles might all seem unlikely candidates, but they are among the deadliest animals in the world. Like the more obvious perilous creatures – venomous snakes, spiders and scorpions – these animals release toxins that dramatically modulate the activity of various targets including ion channels, thereby affecting cellular communication and disrupting normal biochemical and physiological processes in prey or predator.
Animal venom is a complex mixture of various components – inorganic salts, organic molecules like alkaloids, proteins and peptides (). While this concoction enables a multi-pronged attack upon the target organism, it has also led to an entire collection of bio-active compounds being available to researchers for probing the structural and functional properties of their molecular targets. Since ion channels play an essential role in neuronal signaling and muscle contractions, it is unsurprising that many venom toxins have evolved to block or modulate the function of ion channels (). Not only have venom-derived peptides been used extensively in probing ion channels, the understanding of the mechanism of this interaction has also led to the development of venom-based therapeutics targeting various ion channels. In fact, the recognition of animal venom having medicinal benefits is not a recent phenomenon. Venom from various animals had been used as medicines for centuries, in civilizations all over the world (; Utkin, 2015).
Modern medicine has shown conclusively that venoms contain compounds with therapeutic potential. Many of these have been isolated, analyzed for structure and function, and have served as scaffolds for the development of various drugs. Venom peptides have evolved to be highly stable, being able to withstand degradation by proteolytic enzymes in the foreign environment they are injected into and in the venom itself. This stability is conferred by one or more disulfide bridges (Figure 1). While the peptides mutate into more potent and/or selective variants, the structurally important cysteines tend to be highly conserved. Cystine-stabilized α/β fold, inhibitor cystine knot (ICK, or knottin) and the three-finger toxin motif are all highly prevalent motifs in these peptides (Undheim et al., 2016).
FIGURE 1
This mini-review briefly describes exemplar peptides derived from animal venom, which have been used to probe the structure and function of voltage-activated cation channels, as well as are being developed as potential therapeutics (listed in Table 1). Here, we describe ion channels that are selectively permeable to potassium, calcium, and sodium ions.
Table 1
| Channel | Toxin | Species | IC50/Kd | Reference |
|---|---|---|---|---|
| Kir1.1 | Lq2 (α-KTx1.2) | Leiurus quinquestriatus | 410 nM | |
| δ-DTX | Dendroaspis angusticeps | 150 nM | ||
| Tertiapin (TPN) | Apis mellifera | 2 nM | ||
| Kir3.1/Kir3.4 | Tertiapin (TPN) | Apis mellifera | 8 nM | |
| Kv1.1 | α-DTx | Dendroaspis angusticeps | 20 nM | |
| DTx K (toxin I) | Dendroaspis polylepis | 50 nM | Robertson and Owen, 1993 | |
| α-KTx 2.2 (margatoxin) | Centruroides margaritatus | 4.2 nM | ||
| α-KTx 2.5 (hongotoxin) | Centruroides limbatus | 31 pM | ||
| α-KTx 3.13 | Mesobuthus eupeus | 203 pM | ||
| ShK | Stichodactyla helianthus | 16 pM | ||
| Kv1.2 | α-DTx | Dendroaspis angusticeps | 17 nM | |
| α-KTx 1.1 (Charybdotoxin) | Leiurus quinquestriatus hebraeus | 9 nM | Takacs et al., 2009 | |
| α-KTx 10.1 (Cobatoxin-1) | Centruroides noxius | 27 nM | ||
| α-KTx 2.1 (Noxiustoxin) | Centruroides noxius | 2 nM | ||
| α-KTx 2.2 (margatoxin) | Centruroides margaritatus | 6 pM | ||
| α-KTx 2.5 (hongotoxin) | Centruroides limbatus | 0.17 nM | ||
| α-KTx 3.6 (mesomartoxin) | Mesobuthus martensii | 15 nM | Wang et al., 2015 | |
| α-KTx 6.4 | Pandinus imperator | 8 pM | Sarrah et al., 2003 | |
| α-KTx-6.2 (Maurotoxin) | Scorpio maurus palmatus | 0.8 nM | Ryadh et al., 2018 | |
| α-KTx-6.21 (Urotoxin) | Urodacus yaschenkoi | 160 pM | ||
| ShK | Stichodactyla helianthus | 9 nM | ||
| BscTx1 | Bunodosoma caissarum | 30 pM | Orts et al., 2013 | |
| Kv1.3 | α-KTx 6.12 (Anuroctoxin) | Anuroctonus phaiodactylus | 0.73 nM | |
| α-KTx 3.12 (Aam-KTX) | Androctonus amoreuxi | 1.1 nM | ||
| α-KTx 2.1 (Noxiustoxin) | Centruroides noxius | 1 nM | ||
| α-KTx 2.2 (margatoxin) | Centruroides margaritatus | 11 pM | ||
| α-KTx 2.5 (hongotoxin) | Centruroides limbatus | 86 nM | ||
| α-KTx 6.15 (Hemitoxin) | Hemiscorpius lepturus | 2 nM | Najet et al., 2008 | |
| α-KTx 6.3 (Neurotoxin) | Heterometrus spinifer | 12 pM | ||
| α-KTx 3.2 (Agitoxin-2) | Leiurus quinquestriatus hebraeus | 200 pM | ||
| α-KTx 12.5 (LmKTx10) | Lychas mucronatus | 28 nM | ||
| α-KTx 3.11 | Odonthobuthus doriae | 7.2 nM | ||
| α-KTx3.7 | Orthochirus scrobiculosus | 14 pM | Mouhat et al., 2005 | |
| α-KTx 23.1 (Vm24) | Vaejovis mexicanus smithi | 2.9 pM | Varga et al., 2012 | |
| ShK | Stichodactyla helianthus | 11 pM | ||
| Kv1.6 | α-DTx | Dendroaspis angusticeps | 9 nM | Swanson et al., 1990 |
| α-KTx 1.1 (Charybdotoxin) | Leiurus quinquestriatus hebraeus | 22 nM | ||
| α-KTx 3.2 (Agitoxin-2) | Leiurus quinquestriatus hebraeus | 37 pM | ||
| ShK | Stichodactyla helianthus | 165 pM | ||
| BcSTx1/BcSTx2 | Bunodosoma caissarum | 1.3 nM/7.7 nM | Orts et al., 2013 | |
| Kv2.1 | HaTx1 (Hanatoxin) | Grammostola spatulata | 42 nM | Swartz and MacKinnon, 1995 |
| JZTX-III/JZTX-XI | Chilobrachys jingzhao | 710 nM/390 nM | Tao et al., 2013, 2016 | |
| ScTx1 | Stromatopelma calceata | 12.7 nM | ||
| Kv2.2 | ScTx1 | Stromatopelma calceata | 21.4 nM | |
| Kv3.2 | ShK | Stichodactyla helianthus | 6 nM | Yan et al., 2005 |
| Kv3.4 | BDS-I/BDS-II | Anemonia sulcata | 47 nM/56 nM | |
| Kv4.1 | JZTX-XII | Chilobrachys jingzhao | 363 nM | Yuan et al., 2007 |
| Kv4.2 | PaTx1/PaTx2 | Phrixotrichus auratus | 5 nM/34 nM | |
| ScTx1 | Stromatopelma calceata | 1.2 nM | ||
| TsTx-Kβ (Ts8) | Tityus serrulatus | 652 nM | Pucca et al., 2016 | |
| HpTx3 (Heteropodatoxin) | Heteropoda venatoria | 67 nM | Sanguinetti et al., 1997 | |
| JZTX-V | Chilobrachys jingzhao | 604.2 nM | Zeng et al., 2007 | |
| Kv4.3 | PaTx1/PaTx2 | Phrixotrichus auratus | 28 nM/71 nM | |
| SNX-482 | Hysterocrates gigas | 3 nM | ||
| KCa1.1 | α-KTx1.1 (Charybdotoxin) | Leiurus quinquestriatus | 2.9 nM | Rauer et al., 2000 |
| α-KTx 1.3 (Iberiotoxin) | Mesobuthus tamulus | 1.7 nM | ||
| α-KTx 1.5 (BmTx1) | Buthus martensi Karsch | 0.6 nM | Romi-Lebrun et al., 1997 | |
| α-KTx 1.6 (BmTx2) | Buthus martensi Karsch | 0.3 nM | Romi-Lebrun et al., 1997 | |
| α-KTx 1.11 (Slotoxin) | Centruroides noxius | 1.5 nM | ||
| α-KTx 3.1 (Kaliotoxin) | Androctonus mauretanicus | 20 nM | ||
| α-KTx 3.5 (Kaliotoxin2) | Androctonus australis | 135 nM | ||
| α-KTx 12.1 (Butantoxin) / TsTX-IV | Tityus serrulatus | 50 nM | Novello et al., 1999 | |
| α-KTx (BmP09) | Buthus martensi Karsch | 27 nM | Yao et al., 2005 | |
| Natrin | Naja naja atra | 34.4 nM | Wang et al., 2005 | |
| KCa2.1 | α-KTx 5.1 (Leiurotoxin I/scyllatoxin) | Leiurus quinquestriatus hebraeus | 325 nM | |
| Tamapin | Mesobuthus tamulus | 32 nM | Pedarzani et al., 2002 | |
| Apamin | Apis mellifera | 8 nM | ||
| KCa2.2 | α-KTx 5.1 (Leiurotoxin I/scyllatoxin) | Leiurus quinquestriatus hebraeus | 200 pM | |
| PO5 | Androctonus mauretanicus | 22 nM | Zerrouk et al., 1993 | |
| Tamapin | Mesobuthus tamulus | 24 pM | Pedarzani et al., 2002 | |
| Apamin | Apis mellifera | 30-200 pM | ||
| TsK | Tityus serrulatus | 80 nM | ||
| KCa2.3 | α-KTx 5.1 (Leiurotoxin I/scyllatoxin) | Leiurus quinquestriatus hebraeus | 1.1 nM | |
| PO5 | Androctonus mauretanicus | 25 nM | Zerrouk et al., 1993 | |
| Tamapin | Mesobuthus tamulus | 1.7 nM | Pedarzani et al., 2002 | |
| Apamin | Apis mellifera | 10 nM | ||
| TsK | Tityus serrulatus | 197 nM | ||
| KCa3.1 | α-KTx 1.1 (Charybdotoxin) | Leiurus quinquestriatus hebraeus | 5 nM | ; Rauer et al., 2000 |
| α-KTx 6.2 (Maurotoxin) | Maurus palmatus | 1 nM | ||
| Margatoxin | Centruroides margaritatus | 459 nM | ||
| α-KTx 3.7 (OSK1) | Orthochirus scrobiculosus | 225 nM | Mouhat et al., 2005 | |
| ShK | Stichodactyla helianthus | 30 nM | Pennington et al., 1995 | |
| BgK | Bunodosoma granulifera | 172 nM | ||
| Nav1.1 | MeuNaTxα-12 | Mesobuthus eupeus | 0.91 μM | Zhu et al., 2012 |
| MeuNaTxα-13 | Mesobuthus eupeus | 2.5 μM | Zhu et al., 2012 | |
| ATX-II | Anemonia sulcata | 6 nM | ; Oliveira et al., 2004 | |
| Cangitoxin-II; CGTX-II | Bunodosoma cangicum | 0.165 μM | Zaharenko et al., 2012 | |
| Bc-III | Bunodosoma caissarum | 300 nM | Oliveira et al., 2004 | |
| AFT-II | Anthopleura fuscoviridis | 391 nM | Oliveira et al., 2004 | |
| GVIIJSSG | Conus geographus | 11 nM | ||
| μ-Conotoxin BuIIIA | Conus bullatus | 0.35 μM | Wilson et al., 2011 | |
| Nav1.2 | Huwentoxin IV | Haplopelma schmidti | 150 nM | Minassian et al., 2013 |
| ATX-II | Anemonia sulcata | 41 nM | Oliveira et al., 2004 | |
| Bc-III | Bunodosoma caissarum | 1449 nM | Oliveira et al., 2004 | |
| AFT-II | Anthopleura fuscoviridis | 1998 nM | Oliveira et al., 2004 | |
| Lqh-2 | Leiurus quinquestriatus hebraeus | 1.8 nM | ||
| PnTx1 | Phoneutria nigriventer | 33.7 nM | Silva et al., 2012 | |
| Phrixotoxin 3 (PaurTx3) | Phrixotrichus auratus | 0.6 nM | ||
| ProTx-III | Thrixopelma pruriens | 0.3 μM | ||
| Hainantoxin-IV | Ornithoctonus hainana | 36 nM | ||
| GrTx1 | Grammostola rosea | 0.23 μM | Redaelli et al., 2010 | |
| GVIIJSSG | Conus geographus | 11 nM | ||
| μ-conotoxin TIIIA | Conus tulipa | 0.045 μM | Wilson et al., 2011 | |
| μ-conotoxin SIIIA | Conus striatus | 0.05 μM | Wilson et al., 2011 | |
| μ-conotoxin KIIIA | Conus kinoshitai | 0.003 μM | Wilson et al., 2011 | |
| μ-conotoxin MIIIA | Conus magus | 0.45 μM | Wilson et al., 2011 | |
| μ-conotoxin BuIIIA | Conus bullatus | 0.012 μM | Wilson et al., 2011 | |
| Nav1.3 | AFT-II | Anthopleura fuscoviridis | 460 nM | Oliveira et al., 2004 |
| ATX-II | Anemonia sulcata | 759 nM | Oliveira et al., 2004 | |
| Bc-III | Bunodosoma caissarum | 1458 nM | Oliveira et al., 2004 | |
| ProTx-III | Thrixopelma pruriens | 0.9 μM | ||
| Hainantoxin-IV | Ornithoctonus hainana | 375 nM | ||
| GrTx1 | Grammostola rosea spider | 0.77 μM | Redaelli et al., 2010 | |
| GVIIJSSG | Conus geographus | 15 nM | ||
| μ-conotoxin BuIIIA | Conus bullatus | 0.35 μM | Wilson et al., 2011 | |
| Nav1.4 | AFT-II | Anthopleura fuscoviridis | 31 nM | Oliveira et al., 2004 |
| ATX-II | Anemonia sulcata | 109 nM | Oliveira et al., 2004 | |
| Bc-III | Bunodosoma caissarum | 821 nM | Oliveira et al., 2004 | |
| MrVIB (μO-Conotoxin) | Conus marmoreus | 222 nM | Zorn et al., 2006 | |
| MfVIA (μO-Conotoxin) | Conus magnificus | 81 nM | Vetter et al., 2012 | |
| GrTx1 | Grammostola rosea | 1.3 μM | Redaelli et al., 2010 | |
| GVIIJSSG | Conus geographus | 47 nM | ||
| μ-conotoxin TIIIA | Conus tulipa | 0.005 μM | Wilson et al., 2011 | |
| μ-conotoxin SIIIA | Conus striatus | 0.13 μM | Wilson et al., 2011 | |
| μ-conotoxin MIIIA | Conus magus | 0.33 μM | Wilson et al., 2011 | |
| μ-conotoxin BuIIIA | Conus bullatus | 0.012 μM | Wilson et al., 2011 | |
| Nav1.5 | ProTx-II | Thrixopelma pruriens | 79 nM | Middleton et al., 2002 |
| ATX-II | Anemonia sulcata | 49 nM | Oliveira et al., 2004 | |
| AFT-II | Anthopleura fuscoviridis | 62.5 nM | Oliveira et al., 2004 | |
| Bc-III | Bunodosoma caissarum | 307 nM | Oliveira et al., 2004 | |
| CGTX-II | Bunodosoma cangicum | 50 nM | Zaharenko et al., 2012 | |
| Nav1.6 | ATX-II | Anemonia sulcata | 180 nM | Oliveira et al., 2004 |
| AFT-II | Anthopleura fuscoviridis | 300 nM | Oliveira et al., 2004 | |
| Bc-III | Bunodosoma caissarum | 900 nM | Oliveira et al., 2004 | |
| ProTx-II | Thrixopelma pruriens | 47 nM | ||
| CGTX-II | Bunodosoma cangicum | 50 nM | Zaharenko et al., 2012 | |
| ProTx-III | Thrixopelma pruriens | 0.29 μM | ||
| GrTx1 | Grammostola rosea spider | 0.63 μM | Redaelli et al., 2010 | |
| Nav1.7 | ProTx-I | Thrixopelma pruriens | 51 nM | Middleton et al., 2002 |
| ProTx-II | Thrixopelma pruriens | 300 pM | Schmalhofer et al., 2008 | |
| ProTx-III | Thrixopelma pruriens | 2.1 nM | ||
| Lqh-2 | Leiurus quinquestriatus hebraeus | 32 nM | ||
| Lqh-3 | Leiurus quinquestriatus hebraeus | 13.6 nM | ||
| GpTx-1 | Grammostola porteri | 10 nM | Murray et al., 2015 | |
| μ-SLPTX-Ssm6a | Scolopendra subspinipes mutilans | 25 nM | Yang et al., 2013 | |
| Hainantoxin-IV | Ornithoctonus hainana | 21 nM | ||
| μ-TRTx-Pn3a | Pamphobeteus nigricolor | 0.9 nM | ||
| GrTx1 | Grammostola rosea | 0.37 μM | Redaelli et al., 2010 | |
| GVIIJSSG | Conus geographus | 41 nM | ||
| Huwentoxin-IV | Haplopelma schmidti | 26 nM; 0.4 nM | Xiao et al., 2008; Rahnama et al., 2017 | |
| Nav1.8 | ProTx-I | Thrixopelma pruriens | 27 nM | Middleton et al., 2002 |
| MrVIB (μO-Conotoxin) | Conus marmoreus | 102 nM | ||
| MfVIA (μO-Conotoxin) | Conus magnificus | 529 nM | Vetter et al., 2012 | |
| HSTX-I | Haemadipsa sylvestris | 2.44 μM | Wang et al., 2018 | |
| Nav1.9 | HSTX-I | Haemadipsa sylvestris | 3.30 μM | Wang et al., 2018 |
| Cav1.2 | Calciseptine | Dendroaspis polylepis polylepis | 430 nM | |
| Cav2.1 | ω-conotoxin CVIB | Conus catus | 7.7 nM | |
| ω-conotoxin CVIC | Conus catus | 7.6 nM | ||
| ω-conotoxin MVIIC | Conus magus | 7 nM | ||
| ω-agatoxin IVA | Agelenopsis aperta | 0.1 μM | Mintz et al., 1992 | |
| ω-grammotoxin SIA | Grammostola rosea | 50 nM | ; | |
| Cav2.2 | ω-agatoxin IIA | Agelenopsis aperta | 10 nM | ; |
| ω-agatoxin IIIA | Agelenopsis aperta | 1.4 nM | ; Olivera et al., 1994 | |
| ω-agatoxin IIIB | Agelenopsis aperta | 140 nM | ; Yan and Adams, 2000 | |
| ω-agatoxin IIID | Agelenopsis aperta | 35 nM | ||
| ω-ctenitoxin-Pn3a/Neurotoxin Tx3–4 | Phoneutria nigriventer | 50 pM | ||
| ω-conotoxin CVIA | Conus catus | 0.6 nM | ||
| ω-conotoxin CVIB | Conus catus | 7.7 nM | ||
| ω-conotoxin CVIC | Conus catus | 7.6 nM | ||
| ω-conotoxin CVID | Conus catus | 0.07 nM | ||
| ω-conotoxin MVIIA | Conus magus | 0.055 nM | ||
| ω-conotoxin GVIA | Conus geographus | 0.04 nM | Olivera et al., 1984; | |
| Cav2.3 | SNX482 | Hysterocrates gigas | 15–30 nM | Newcomb et al., 1998 |
| Cav3.1 | Kurtoxin | Parabuthus transvaalicus | 15–50 nM | ; Sidach and Mintz, 2002 |
| ProTx1 | Thrixopelma pruriens | 200 nM | Ohkubo et al., 2010 | |
| Cav3.2 | Kurtoxin | Parabuthus transvaalicus | 25–50 nM | ; Sidach and Mintz, 2002 |
Venom-derived peptide modulators of cation channels.
Venom Peptides Targeting Potassium Channels
Potassium ion channels are of high therapeutic value due to their broad and active presence in a variety of human tissue. To date, numerous disease conditions in neuronal, cardiac, immune, and endocrine systems have been reported to be directly associated with malfunction of potassium channels. Potassium channels are categorized into four families: two transmembrane (TM) Kir channels, four TM, two pore-domain K2P channels, and six TM Kv and KCa channels (). Here, we discuss the Kir, Kv and KCa channels. The K2P family of channels contribute to voltage-independent “leak” K+ current, and are structurally different from other classes of K+ channels in that they assemble as ‘dimer of dimers’ (). No venom-derived peptide toxins have been reported for K2P channels yet ().
Inwardly rectifying potassium (Kir) channels were first described in 1949 in frog skeletal muscles (), however, they were not cloned and isolated until 1993 (; ). As the name suggests, Kir channels inwardly rectify outward K+ current, allowing extracellular K+ to readily flow into the cells. The unique molecular mechanism is due to the intracellular binding of Mg2+ and polyamines (). Kir channels are homo- or hetero- tetrameric structures assembled from four Kir subunits, containing two TM segments separated by a selectivity filter region (Whorton and MacKinnon, 2011; ). Structural, functional and pathophysiological details of four specific types of Kir channels have been detailed elsewhere ().
The peptides that show high affinity toward Kir channels (IC50 < 0.5 μM) are scorpion toxin ChTx2 (α-KTx1.2), snake toxin δ-dendrotoxin (δ-DTX), and honey bee toxin Tertiapin (TPN) (; ; ; ). Like many other venom toxins, these three molecules are rich in cysteine and positively charged residues. Computational simulation and docking studies have hypothesized binding mechanisms of these toxins (). Positively charged residues from toxin come into close contact with negatively charged residues on channel pore region, strengthening electrostatic interactions between the two. Hydrophobic forces between aliphatic residues also count into binding affinity.
TPN and TPNM13Q are considered the most potent inhibitors. TPN binds to Kir1.1 and Kir3.1/3.4 at 2-8 nM (EC50), thus being an ideal tool for investigations of Kir channels’ functional and pharmacological properties (; Walsh, 2011). TPN has shown potential therapeutic use in a canine model, treating atrial fibrillation, without causing ventricle arrhythmia (). More recently, TPN, together with sodium channel blockers, has been shown to have synergistic effects in preventing atrial fibrillation and prolonging atrial effective refractory period. The combination formula has been patented for medication manufacturing by Gilead Sciences.
Voltage-gated potassium (Kv) channels tightly control membrane permeability of K+ by sensing voltage change, thereby playing a key role in regulating action potential and propagating electrical signals in excitable cells (Yellen, 2002). In non-excitable cells, Kv channels modulate cellular metabolism and facilitate downstream signaling cascade; for example, Kv1.3 in T lymphocytes (). 40 Kv channels in 12 subfamilies have been found and many extensively studied (). Kv channels are homo- or hetero- tetramers, made up of four subunits each consisting of six TM helices. Voltage sensing domain (VSD) (S1–S4) is connected to pore domain (S5–S6) through S4–S5 intracellular loop, driving the pore to open or close ().
Research on venom peptide modulators of Kv channels started in 1980s, and to date more than 200 peptides with inhibitory effect on Kv channels have been identified (; ). These polypeptides usually bind to Kv channels in two unique mechanisms. The pore blockers sit in the shallow vestibule at extracellular pore region, while the gating modifiers bind to the so-called “paddle motif” of the VSD accessible from the extracellular side.
Scorpion toxin charybdotoxin (ChTx) was one of the earliest venom toxins used as an important research tool to understand Kv channel subunit stoichiometry (), auxiliary beta subunits (), as well as its overall architecture ().
Sea anemone toxin ShK blocks Kv channels at nanomolar to sub-nanomolar potency (; ). ShK and its analogs are blockers of the Kv channel pore. They bind to all four subunits in the channel tetramer by two key interactions within the external vestibule – Lys22 occludes the channel pore like a “cork in a bottle,” and Tyr23, together with Lys22, forms a “functional dyad” required for channel block. Many K+ channel-blocking peptides exhibit similar blocking mechanism, consisting of a dyad of lysine and neighboring aromatic/aliphatic residue (). With the goal of developing a highly selective Kv1.3 inhibitor, nearly 10 years of effort was made to re-engineer the native ShK. In 2006, a stable analog, ShK-186 demonstrated specific binding to Kv1.3 at 69 pM, which is 100-fold selective to other Kv channels (). ShK-186 (Dalazatide), now being developed by Kineta, has passed phase I clinical trials It is the only venom-derived peptide blocking K+ channels that is being developed as a therapeutic (Tarcha et al., 2012, Tarcha et al., 2017).
The hERG channel (or Kv11.1) plays a crucial role in the cardiac action potential by repolarizing IKr current, the rapid component of the delayed rectifier potassium current. While selective Kv11.1-blockers are available (e.g., BeKm-1 from scorpion Mesobuthus eupeus) (), it warrants special attention as many drugs/peptides intended for other targets, can exhibit non-selective binding to it, with potentially fatal consequences. Inhibition of hERG by drugs can lead to lengthening of the electrocardiographic QT interval, while hERG channel activators can cause drug-induced short QT syndrome. Both cases can lead to potentially fatal arrhythmias. Hence, FDA guidelines recommend that all drugs that are intended for human use be evaluated for anti-hERG activity (Vandenberg et al., 2012).
Calcium (Ca2+)-activated potassium channels (KCa) are broadly divided into three subtypes based on their single channel conductance - big conductance (BKCa), intermediate conductance (IKCa) and small conductance (SKCa). While the BKCa channels are activated by both voltage and increase in cytosolic Ca2+, the IKCa and SKCa channels are activated exclusively by the latter. Like Kir and Kv channels, the KCa channels are tetramers made up of four α subunits. BKCa requires additional regulatory subunits, and is made up of 6/7 TM segments, while SKCa and IKCa contain 6 TM segments, with a calmodulin molecule bound to each subunit, serving as the Ca2+ sensor. One of the first peptide toxins that were found to inhibit K+ channels included apamin (derived from bee venom) and charybdotoxin (ChTX, derived from the scorpion venom) (; Rauer et al., 2000). Apamin blocks SK channels (KCa2), and served as a primary pharmacological tool to distinguish between KCa2 channels and KCa1.1/KCa3.1. ChTX inhibits both KCa channels (KCa1.1 and KCa3.1) and Kv channels (Kv1.2, Kv1.3, and Kv1.6). Another scorpion toxin iberiotoxin is selective for BK channel (KCa1.1) ().
Venom Peptides Targeting Voltage-Gated Sodium Channels
Voltage-gated sodium (Nav) channels are present in the membranes of most excitable cells and are responsible for initiation and propagation of action potentials. Studies elucidating details of ion selectivity, hypothesizing the Nav pore diameter and binding mechanism of sodium-channel acting local anesthetics and related drugs, were bolstered by the availability of ion channel toxins, like the alkaloids tetrodotoxin (TTX) and saxitoxin (STX) (, , ; ). Studies to isolate and purify the Nav channel protein were pioneered by William Catterall and co-workers using, besides TTX and STX, scorpion toxin (ScTx) neuropeptides (; ; ).
Nav channels are divided into nine subtypes (Nav1.1–Nav1.9) based on their sequence, TTX binding and tissue expression. The 250 kDa channel-forming α-subunits are pseudo-tetrameric, wherein a single polypeptide chain folds into four homologous, non-identical domains (DI–IV), each containing six TM segments (S1–S6). The S5–S6 segments from all four domains form the central ion pore, while the S1–S4 segments in each domain form the VSD. A single channel is composed of one pore-forming α subunit, which may be associated with either one or two β subunits. The α subunit is functional on its own, and forms the core of the channel.
The venom of various animals contain toxins that target Nav channels to attack the neuromuscular systems of their adversaries and prey. Toxins that modulate Nav channel function generally do so in two ways – either by blocking the flow of Na+ ions through the pore, or by modifying the gating mechanisms.
One of the best studied pore blockers for Nav channels are the μ-conotoxin peptides from cone snails. Conotoxins are disulfide-rich peptides that are isolated from the venom of cone snails (genus Conus). Venom derived from cone snails is a treasure trove of peptide toxins for different ion channels and other receptor proteins (Olivera et al., 1985, 1990). M-conotoxins demonstrate the best binding with the skeletal muscle isoform of Nav channel, Nav1.4, with variable binding to other isoforms. These variations in targeting selectivity and affinity of each peptide for the different Nav isoforms constitute an important tool for distinguishing between different isoforms (Zhang et al., 2013). On the other hand are toxin peptides that modify Nav channel gating by interacting with the voltage sensors. Various classes of conotoxins interact with the voltage sensors of Nav channels and influence their gating properties. Δ-conotoxins are ubiquitously expressed in a range of cone snail venoms and inhibit fast inactivation of channels. While the μ-conotoxins are pore-blocking peptides, the μO-conotoxins are gating modifiers that target the voltage sensors and inhibit channel opening (; Zorn et al., 2006; ). MO-conotoxins were evaluated for their pain-relieving activity and found to be anti-nociceptive in animal models of pain (Teichert et al., 2012).
Several spider toxins are in pre-clinical development stage as antagonists of Nav1.7, an attractive target for development of non-opiod pain medication. Protoxin-II (ProTX-II), derived from the tarantula Thrixopelma pruriens, inhibits channel activation by shifting to positive potentials the voltage dependence of channel activation. Using ProTX-II as a scaffold, a highly potent and selective Nav1.7 blocking peptide (JNJ63955918) has been developed, the effect of which mirrors features of the Nav1.7-null phenotype (). Another venom peptide, huwentoxin IV, is derived from the Chinese bird-eating spider Selenocosmia huwena (Peng et al., 2002). This peptide preferentially inhibits Nav1.7 by binding one of the four VSDs of the channel, making it more selective as compared to the local anesthetics that bind the conserved channel pore (Ragsdale et al., 1996; Xiao et al., 2008, 2011). Various mutational studies led to a triple mutant of huwentoxin IV (E1G, E4G, and Y33W) being developed with a very high potency toward Nav1.7 blocking (Revell et al., 2013).
Nav1.5 is expressed mainly in cardiac muscle, where it mediates fast depolarization phase of the cardiac action potential and is a target for class I anti-arrhythmic agents. Jingzhaotoxin-III (from the Chinese tarantula Chilobrachys jingzhao) selectively inhibits the activation of Nav1.5 in heart cells (IC50 ∼ 350 nM), but not Nav neuronal subtypes (Rong et al., 2011).
Sea anemones are another source of Nav-targeting peptides. Some key toxins are ATX-II (from Anemonia sulcata), AFT-II (from Anthopleura fuscoviridis) and Bc-III (from Bunodosoma caissarum). ATX-II strongly affects Nav1.1 and Nav1.2, while AFT-II affects Nav1.4 and Nav1.5. Given that these two differ in a single amino acid (ATX-II→K36A→AFTII), indicates that the lysine at position 36 is important for the very strong effects of ATX-II on Nav1.1/2 channels (Oliveira et al., 2004; Moran et al., 2009).
Venom Peptides Targeting Voltage-Gated Calcium Channels
Voltage-gated calcium channels (Cav) facilitate cellular calcium influx in response to membrane depolarization. They regulate hormone secretion, neurotransmitter release, propagation of cardiac action potential, muscle contraction and gene expression in different cell types (Catterall, 2011).
Similar to the Nav channels, the α1 subunit of Cav channels is organized in four homologous domains (I–IV), each containing six TM segments (S1–S6). The S1–S4 segments constitute the voltage sensor, while S5–S6 constitute the pore. Auxiliary subunits usually associate with α1, regulating channel expression and function. Cav channels are grouped into various types based on their electrophysiological and pharmacological properties and tissue distribution – L-type (Cav1 subfamily: Cav1.1-Cav1.4); P/Q-, N-, and R-types (Cav2.1, Cav2.2 and Cav2.3, respectively) and T-type (Cav3 subfamily: Cav3.1-Cav3.3). Venom toxins have played a vital role in the discovery of, and in deciphering the structure and function of, many Cav channels. Chief among them are the ω-conotoxins and ω-agatoxins.
Ω-conotoxins are ∼24–30 residues in length and contain three intramolecular disulfide bonds. They target Cav channels via blocking the ion pore. Ω-conotoxin GVIA, from the venom of Conus geographus, was the first of the ω-conotoxins to be isolated and characterized (; Olivera et al., 1985). Studies with GVIA showed inhibition of Ca2+ entry (voltage-activated), and GVIA was a powerful probe to explore the presynaptic terminal, linking Cav (N-type) channels to neurotransmitter release and synaptic transmission (; Olivera et al., 1984). Molecular identity of the N-type and L-type channel subunit composition was determined using GVIA binding (Williams et al., 1992).
Subsequent to GVIA, many other ω-conotoxins were identified. One of the most prominent ones is MVIIA, from the Magician’s cone snail, Conus magus (Olivera et al., 1987), which was tested and developed as a therapeutic agent against pain. Ziconotide (Prialt®) has been clinically approved for the treatment of severe chronic pain associated with cancer and neuropathies, and is currently the only venom peptide drug targeting a voltage-gated ion channel (Cav2.2) that is in clinical use (Miljanich, 2004). A more selective ω-conotoxin, CVID, was isolated from Conus catus (), and was being developed as leconotide for pain treatment. However, it failed clinical trials due to adverse side-effects ().
Spider toxin ω-agatoxin IVA, a gating modifier toxin isolated from Agelenopsis aperta, specifically targets P/Q-type channels (Pringos et al., 2011), and was used to study the channel subunit composition (; Witcher et al., 1995).
Concluding Remarks
Given that there are many species whose toxic venom are yet to be fully explored, the collection of venom-derived peptides to be discovered is immense. Also, with the advent of technology in drug design, based on currently available toxin peptides, new drugs will be developed into more stable and selective biologics. While venomous species developed toxins to incapacitate prey and predators, and envenomation is a public health hazard for us humans, the toxins have proven to be an excellent source of research and therapeutic tools.
Statements
Author contributions
All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.
Funding
SB has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no 608765. The authors also acknowledge support from Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2016-T2-2-032) and Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Start-Up Grant to Prof. George K. Chandy.
Acknowledgments
The authors thank Prof. George K. Chandy and Dr. Jeff Chang for helpful discussions.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
AbbasN.BelghaziM.Abdel-MottalebY.TytgatJ.BougisP. E.Martin-EauclaireM.-F. (2008). A new Kaliotoxin selective towards Kv1.3 and Kv1.2 but not Kv1.1 channels expressed in oocytes.Biochem. Biophys. Res. Commun.376525–530. 10.1016/j.bbrc.2008.09.033
2
Abdel-MottalebY.VandendriesscheT.ClynenE.LanduytB.JalaliA.VatanpourH.et al (2008). OdK2, a Kv1.3 channel-selective toxin from the venom of the Iranian scorpion Odonthobuthus doriae.Toxicon511424–1430. 10.1016/j.toxicon.2008.03.027
3
AdamsM. E.BindokasV. P.HasegawaL.VenemaV. J. (1990). Omega-agatoxins: novel calcium channel antagonists of two subtypes from funnel web spider (Agelenopsis aperta) venom.J. Biol. Chem.265861–867.
4
AgnewW. S.LevinsonS. R.BrabsonJ. S.RafteryM. A. (1978). Purification of the tetrodotoxin-binding component associated with the voltage-sensitive sodium channel from Electrophorus electricus electroplax membranes.Proc. Natl. Acad. Sci. U.S.A.752606–2610. 10.1073/pnas.75.6.2606
5
AlexanderS. P. H.StriessnigJ.KellyE.MarrionN. V.PetersJ. A.FaccendaE.et al (2017). The concise guide to pharmacology 2017/18: voltage-gated ion channels.Br. J. Pharmacol.174S160–S194. 10.1111/bph.13884
6
ArmstrongC. M.BezanillaF.RojasE. (1973). Destruction of sodium conductance inactivation in squid axons perfused with pronase.J. Gen. Physiol.62375–391. 10.1085/jgp.62.4.375
7
BagdáanyM.BatistaC. V. F.Valdez-CruzN. A.SomodiS.de la VegaR. C. R.LiceaA. F.et al (2005). Anuroctoxin, a new scorpion toxin of the α-KTx 6 subfamily, is highly selective for Kv1.3 over IKCa1 ion channels of human T lymphocytes.Mol. Pharmacol.671034–1044. 10.1124/mol.104.007187
8
BartokA.TothA.SomodiS.SzantoT. G.HajduP.PanyiG.et al (2014). Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels.Toxicon876–16. 10.1016/j.toxicon.2014.05.002
9
BeneskiD. A.CatterallW. A. (1980). Covalent labeling of protein components of the sodium channel with a photoactivable derivative of scorpion toxin.Proc. Natl. Acad. Sci. U.S.A.77639–643. 10.1073/pnas.77.1.639
10
BhattacharjeeP.BhattacharyyaD. (2014). Therapeutic use of snake venom components: a voyage from ancient to modern India.Mini. Rev. Org. Chem.1145–54. 10.2174/1570193X1101140402101043
11
BindokasV. P.AdamsM. E. (1989). ω-Aga-I: a presynaptic calcium channel antagonist from venom of the funnel web spider, Agelenopsis aperta.J. Neurobiol.20171–188. 10.1002/neu.480200402
12
BosmansF.RashL.ZhuS.DiochotS.LazdunskiM.EscoubasP. T.et al (2006). Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes.Mol. Pharmacol.69419–429. 10.1124/mol.105.015941
13
CahalanM. D.ChandyK. G. (2009). The functional network of ion channels in T lymphocytes.Immunol. Rev.23159–87. 10.1111/j.1600-065X.2009.00816.x
14
CandiaS.GarciaM. L.LatorreR. (1992). Mode of action of iberiotoxin, a potent blocker of the large conductance Ca2+)-activated K+ channel.Biophys. J.63583–590. 10.1016/S0006-3495(92)81630-2
15
CarboneE.WankeE.PrestipinoG.PossaniL. D.MaelickeA. (1982). Selective blockage of voltage-dependent K+ channels by a novel scorpion toxin.Nature29690–91. 10.1038/296090a0
16
CardosoF. C.DekanZ.RosengrenK. J.EricksonA.VetterI.DeuisJ. R.et al (2015). Identification and characterization of ProTx-III [ -TRTX-Tp1a], a new voltage-gated sodium channel inhibitor from venom of the tarantula Thrixopelma pruriens.Mol. Pharmacol.88291–303. 10.1124/mol.115.098178
17
CastañedaO.SotolongoV.AmorA. M.StöcklinR.AndersonA. J.HarveyA. L.et al (1995). Characterization of a potassium channel toxin from the Caribbean sea anemone Stichodactyla helianthus.Toxicon33603–613. 10.1016/0041-0101(95)00013-C
18
CastleN. A. (2003). Maurotoxin: a potent inhibitor of intermediate conductance Ca2+-activated potassium channels.Mol. Pharmacol.63409–418. 10.1124/mol.63.2.409
19
CastleN. A.StrongP. N. (1986). Identification of two toxins from scorpion (Leiurus quinquestriatus) venom which block distinct classes of calcium-activated potassium channel.FEBS Lett.209117–121. 10.1016/0014-5793(86)81095-X
20
CatterallW. A. (2011). Voltage-gated calcium channels. Cold Spring Harb. Perspect. Biol. 3:a003947. 10.1101/cshperspect.a003947
21
ChahineM.PlanteE.KallenR. G. (1996). Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel α-subunits expressed in tsA201 cells.J. Membr. Biol.15239–48. 10.1007/s002329900083
22
ChangS.BajajS.ChandyK. (2018). ShK toxin: history, structure and therapeutic applications for autoimmune diseases.WikiJ. Sci.1:3. 10.15347/wjs/2018.003
23
ChenH.LuS. Q.LeipoldE.GordonD.HanselA.HeinemannS. H. (2002). Differential sensitivity of sodium channels from the central and peripheral nervous system to the scorpion toxins Lqh-2 and Lqh-3.Eur. J. Neurosci.16767–770. 10.1046/j.1460-9568.2002.02142.x
24
ChiV.PenningtonM. W.NortonR. S.TarchaE. J.LondonoL. M.Sims-FaheyB.et al (2012). Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases.Toxicon59529–546. 10.1016/j.toxicon.2011.07.016
25
ChuanT.RuixinZ.LixinZ.TianyiQ.ZhiweiC.TingguoK. (2013). Potassium channels: structures, diseases, and modulators.Chem. Biol. Drug Des.831–26. 10.1111/cbdd.12237
26
ChuangR. S.JaffeH.CribbsL.Perez-ReyesE.SwartzK. J. (1998). Inhibition of T-type voltage-gated calcium channels by a new scorpion toxin.Nat. Neurosci.1668–674. 10.1038/3669
27
Cordeiro MdoN.de FigueiredoS. G.ValentimA.doC.DinizC. R.von EickstedtV. R. D.et al (1993). Purification and amino acid sequences of six Tx3 type neurotoxins from the venom of the Brazilian “armed” spider Phoneutria Nigriventer (keys.).Toxicon3135–42. 10.1016/0041-0101(93)90354-L
28
CottonJ.CrestM.BouetF.AlessandriN.GolaM.ForestE.et al (1997). A potassium-channel toxin from the sea anemone Bunodosoma granulifera, an inhibitor for Kv1 channels. Revision of the amino acid sequence, disulfide-bridge assignment, chemical synthesis, and biological activity.Eur. J. Biochem.244192–202. 10.1111/j.1432-1033.1997.00192.x
29
CrestM.JacquetG.GolaM.ZerroukH.BenslimaneA.RochatH.et al (1992). Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca2+-activated K+ channels characterized from Androctonus mauretanicus venom.J. Biol. Chem.2671640–1647. 10.2106/JBJS.F.00758
30
DalyN. L.EkbergJ. A.ThomasL.AdamsD. J.LewisR. J.CraikD. J. (2004). Structures of μO-conotoxins from Conus marmoreus: inhibitors of tetrodotoxin (ttx)-sensitive and ttx-resistant sodium channels in mammalian sensory neurons.J. Biol. Chem.27925774–25782. 10.1074/jbc.M313002200
31
de WeilleJ. R.SchweitzH.MaesP.TartarA.LazdunskiM. (1991). Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel.Proc. Natl. Acad. Sci. U.S.A.882437–2440. 10.1073/pnas.88.6.2437
32
DeuisJ. R.DekanZ.WingerdJ. S.SmithJ. J.MunasingheN. R.BholaR. F.et al (2017). Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a.Sci. Rep.7:40883. 10.1038/srep40883
33
DiochotS.DriciM.-D.MoinierD.FinkM.LazdunskiM. (1999). Effects of phrixotoxins on the Kv4 family of potassium channels and implications for the role of I(to1) in cardiac electrogenesis.Br. J. Pharmacol.126251–263. 10.1038/sj.bjp.0702283
34
DiochotS.SchweitzH.BéressL.LazdunskiM. (1998). Sea anemone peptides with a specific blocking activity against the fast inactivating potassium channel Kv3.4.J. Biol. Chem.2736744–6749. 10.1074/jbc.273.12.6744
35
DobrevD.FriedrichA.VoigtN.JostN.WettwerE.ChristT.et al (2005). The G protein-gated potassium current IK,ACh is constitutively active in patients with chronic atrial fibrillation.Circulation1123697–3706. 10.1161/CIRCULATIONAHA.105.575332
36
DoupnikC. A. (2017). Venom-derived peptides inhibiting Kir channels: past, present, and future.Neuropharmacology127161–172. 10.1016/j.neuropharm.2017.07.011
37
DutertreS.LewisR. J. (2010). Use of venom peptides to probe ion channel structure and function.J. Biol. Chem.28513315–13320. 10.1074/jbc.R109.076596
38
EkbergJ.JayamanneA.VaughanC. W.AslanS.ThomasL.MouldJ.et al (2006). muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits.Proc. Natl. Acad. Sci. U.S.A.10317030–17035. 10.1073/pnas.0601819103
39
ErtelE. A.WarrenV. A.CohenC. J.SmithM. M.AdamsM. E.GriffinP. R. (1994). Type III ω-agatoxins: a family of probes for similar binding sites on L- and N-type calcium channels.Biochemistry335098–5108. 10.1021/bi00183a013
40
EscoubasP.DiochotS.CélérierM.-L.NakajimaT.LazdunskiM. (2002). Novel tarantula toxins for subtypes of voltage-dependent potassium channels in the Kv2 and Kv4 subfamilies.Mol. Pharmacol.6248–57. 10.1124/mol.62.1.48
41
FlinspachM.XuQ.PiekarzA. D.FellowsR.HaganR.GibbsA.et al (2017). Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor.Sci. Rep.7:39662. 10.1038/srep39662
42
GajewiakJ.AzamL.ImperialJ.WalewskaA.GreenB. R.BandyopadhyayP. K.et al (2014). A disulfide tether stabilizes the block of sodium channels by the conotoxin O -GVIIJ.Proc. Natl. Acad. Sci. U.S.A.1112758–2763. 10.1073/pnas.1324189111
43
GaoB.PeigneurS.TytgatJ.ZhuS. (2010). A potent potassium channel blocker from Mesobuthus eupeus scorpion venom.Biochimie921847–1853. 10.1016/j.biochi.2010.08.003
44
GarciaM. L.Garcia-CalvoM.HidalgoP.LeeA.MacKinnonR. (1994). Purification and characterization of three inhibitors of voltage-dependent K+ channels from Leiurus quinquestriatus var. hebraeus Venom.Biochemistry336834–6839. 10.1021/bi00188a012
45
GarciaM. L.KnausH. G.MunujosP.SlaughterR. S.KaczorowskiG. J. (1995). Charybdotoxin and its effects on potassium channels.Am. J. Physiol.269C1–C10. 10.1152/ajpcell.1995.269.1.C1
46
Garcia-CalvoM.LeonardR. J.NovickJ.StevensS. P.SchmalhoferW.KaczorowskiG. J.et al (1993). Purification, characterization, and biosynthesis of margatoxin, a component of Centruroides margaritatus venom that selectively inhibits voltage-dependent potassium channels.J. Biol. Chem.26818866–18874. 10.1371/journal.pntd.0005212
47
Garcia-ValdesJ.ZamudioF. Z.ToroL.PossanL. D. (2001). Slotoxin, αKTx1.11, a new scorpion peptide blocker of MaxiK channels that differentiates between α and α+β (β1 or β4) complexes.FEBS Lett.505369–373. 10.1016/S0014-5793(01)02791-0
48
GhanshaniS.WulffH.MillerM. J.RohmH.NebenA.GutmanG. A.et al (2000). Up-regulation of the IKCa1 potassium channel during T-cell activation: molecular mechanism and functional consequences.J. Biol. Chem.27537137–37149. 10.1074/jbc.M003941200
49
GoldsteinS. A.BaylissD. A.KimD.LesageF.PlantL. D.RajanS. (2005). International union of pharmacology. LV. nomenclature and molecular relationships of two-p potassium channels.Pharmacol. Rev.57527–540. 10.1124/pr.57.4.12
50
GrissmerS.NguyenA. N.AiyarJ.HansonD. C.MatherR. J.GutmanG. A.et al (1994). Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines.Mol. Pharmacol.451227–1234.
51
HartshorneR. P.CatterallW. A. (1981). Purification of the saxitoxin receptor of the sodium channel from rat brain.Proc. Natl. Acad. Sci. U.S.A.784620–4624. 10.1073/pnas.78.7.4620
52
HashimotoN.YamashitaT.TsuruzoeN. (2006). Tertiapin, a selective IKACh blocker, terminates atrial fibrillation with selective atrial effective refractory period prolongation.Pharmacol. Res.54136–141. 10.1016/j.phrs.2006.03.021
53
HibinoH.InanobeA.FurutaniK.MurakamiS.FindlayI.KurachiY. (2010). Inwardly rectifying potassium channels: their structure, function, and physiological roles.Physiol. Rev.90291–366. 10.1152/physrev.00021.2009
54
HidalgoP.MacKinnonR. (1995). Revealing the architecture of a K+ channel pore through mutant cycles with a peptide inhibitor.Science268307–310. 10.1126/science.7716527
55
HilleB. (1971). The permeability of the sodium channel to organic cations in myelinated nerve.J. Gen. Physiol.58599–619. 10.1085/jgp.58.6.599
56
HilleB. (1975). Ionic selectivity, saturation, and block in sodium channels. A four- barrier model.J. Gen. Physiol.66535–560. 10.1085/jgp.66.5.535
57
HilleB. (1977). Local anesthetics: hydrophilic and hydrophobic pathways for the drug- receptor reaction.J. Gen. Physiol.69497–515. 10.1085/jgp.69.4.497
58
HoK.NicholsC. G.LedererW. J.LyttonJ.VassilevP. M.KanazirskaM. V.et al (1993). Cloning and expression of an inwardly rectifying ATP-regulated potassium channel.Nature36231–38. 10.1038/362031a0
59
HuguesM.RomeyG.DuvalD.VincentJ. P.LazdunskiM. (1982). Apamin as a selective blocker of the calcium-dependent potassium channel in neuroblastoma cells: voltage-clamp and biochemical characterization of the toxin receptor.Proc. Natl. Acad. Sci. U.S.A.791308–1312. 10.1073/pnas.79.4.1308
60
ImredyJ. P.ChenC.MacKinnonR. (1998). A snake toxin inhibitor of inward rectifier potassium channel ROMK1.Biochemistry3714867–14874. 10.1021/bi980929k
61
JinW.LuZ. (1998). A novel high-affinity inhibitor for inward-rectifier K+ channels.Biochemistry3713291–13299. 10.1021/bi981178p
62
JouirouB.MosbahA.VisanV.GrissmerS.M’BarekS.FajlounZ.et al (2004). Cobatoxin 1 from Centruroides noxius scorpion venom: chemical synthesis, three-dimensional structure in solution, pharmacology and docking on K+ channels.Biochem. J.37737–49. 10.1042/BJ20030977
63
KalmanK.PenningtonM. W.LaniganM. D.NguyenA.RauerH.MahnirV.et al (1998). Shk-Dap22, a potent Kv1.3-specific immunosuppressive polypeptide.J. Biol. Chem.27332697–32707. 10.1074/jbc.273.49.32697
64
KatzB. (1949). Les constantes electriques de la membrane du muscle.Arch. Sci. Physiol.3285–299.
65
KerrL. M.YoshikamiD. (1984). A venom peptide with a novel presynaptic blocking action.Nature308282–284. 10.1038/308282a0
66
KimmT.BeanB. P. (2014). Inhibition of A-type potassium current by the peptide toxin SNX-482.J. Neurosci.349182–9189. 10.1523/JNEUROSCI.0339-14.2014
67
KingG. F. (2011). Venoms as a platform for human drugs: translating toxins into therapeutics.Expert Opin. Biol. Ther.111469–1484. 10.1517/14712598.2011.621940
68
KolosovA.GoodchildC. S.CookeI. (2010). CNSB004 (leconotide) causes antihyperalgesia without side effects when given intravenously: a comparison with ziconotide in a rat model of diabetic neuropathic pain.Pain Med.11262–273. 10.1111/j.1526-4637.2009.00741.x
69
KorolkovaY. V.KozlovS. A.LipkinA. V.PluzhnikovK. A.HadleyJ. K.FilippovA. K.et al (2001). An ERG channel inhibitor from the scorpion Buthus eupeus.J. Biol. Chem.2769868–9876. 10.1074/jbc.M005973200
70
KoschakA.BugianesiR. M.MitterdorferJ.KaczorowskiG. J.GarciaM. L.KnausH.-G. (1998). Subunit composition of brain voltage-gated potassium channels determined by hongotoxin-1, a novel peptide derived from Centruroides limbatus Venom.J. Biol. Chem.2732639–2644. 10.1074/jbc.273.5.2639
71
KuboY.BaldwinT. J.Nung JanY.JanL. Y. (1993). Primary structure and functional expression of a mouse inward rectifier potassium channel.Nature362127–133. 10.1038/362127a0
72
KuzmenkovA. I.KrylovN. A.ChugunovA. O.GrishinE. V.VassilevskiA. A. (2016). Kalium: a database of potassium channel toxins from scorpion venom.Database2016:baw056. 10.1093/database/baw056
73
LampeR. A.DefeoP. A.DavisonM. D.YoungJ.HermanJ. L.SpreenR. C.et al (1993). Isolation and pharmacological characterization of omega-grammotoxin SIA, a novel peptide inhibitor of neuronal voltage-sensitive calcium channel responses.Mol. Pharmacol.44451–460.
74
LebrunB.Romi-LebrunR.Martin-EauclaireM. F.YasudaA.IshiguroM.OyamaY.et al (1997). A four-disulphide-bridged toxin, with high affinity towards voltage-gated K+ channels, isolated from Heterometrus spinnifer (Scorpionidae) venom.Biochem. J.328321–327. 10.1042/bj3280321
75
LecomteC.FerratG.FajlounZ.Van RietschotenJ.RochatH.Martin-EauclaireM. F.et al (1999). Chemical synthesis and structure-activity relationships of Ts κ, a novel scorpion toxin acting on apamin-sensitive SK channel.J. Pept. Res.54369–376. 10.1034/j.1399-3011.1999.00107.x
76
LeipoldE.De BieH.ZornS.BorgesA.OliveraB. M.TerlauH.et al (2007). μo-Conotoxins inhibit Navchannels by interfering with their voltage sensors in domain-2.Channels1253–262. 10.4161/chan.4847
77
LewisR. J.NielsenK. J.CraikD. J.LoughnanM. L.AdamsD. A.SharpeI. A.et al (2000). Novel ω-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes.J. Biol. Chem.27535335–35344. 10.1074/jbc.M002252200
78
LiD.ChenR.ChungS. H. (2016). Molecular dynamics of the honey bee toxin tertiapin binding to Kir3.2.Biophys. Chem.21943–48. 10.1016/j.bpc.2016.09.010
79
LiN.WuJ. X.DingD.ChengJ.GaoN.ChenL. (2017). Structure of a pancreatic ATP-sensitive potassium channel.Cell168101.e10–110.e10. 10.1016/j.cell.2016.12.028
80
LiuJ.MaY.YinS.ZhaoR.FanS.HuY.et al (2009). Molecular cloning and functional identification of a new K+ channel blocker, LmKTx10, from the scorpion Lychas mucronatus.Peptides30675–680. 10.1016/j.peptides.2008.11.015
81
LiuZ.DaiJ.ChenZ.HuW.XiaoY.LiangS. (2003). Isolation and characterization of hainantoxin-IV, a novel antagonist of tetrodotoxin-sensitive sodium channels from the Chinese bird spider Selenocosmia hainana.Cell. Mol. Life Sci.60972–978. 10.1007/s00018-003-2354-x
82
LongS. B.CampbellE. B.MackinnonR. (2005). Voltage sensor of Kv1.2: structural basis of electromechanical coupling.Science309903–908. 10.1126/science.1116270
83
LuZ. (2004). Mechanism of rectification in inward-rectifier K+ channels.Annu. Rev. Physiol.66103–129. 10.1146/annurev.physiol.66.032102.150822
84
LuZ.MacKinnonR. (1997). Purification, characterization, and synthesis of an inward-rectifier K+ channel inhibitor from scorpion venom.Biochemistry366936–6940. 10.1021/bi9702849
85
Luna-RamírezK.BartokA.Restano-CassuliniR.Quintero-HernándezV.CoronasF. I. V.ChristensenJ.et al (2014). Structure, molecular modeling, and function of the novel potassium channel blocker urotoxin isolated from the venom of the Australian Scorpion <em>Urodacus yaschenkoi</em>.Mol. Pharmacol.8628–41. 10.1124/mol.113.090183
86
MacKinnonR. (1991). Determination of the subunit stoichiometry of a voltage-activated potassium channel.Nature350232–235. 10.1038/350232a0
87
MaertensC.CuypersE.AmininasabM.JalaliA.VatanpourH.TytgatJ. (2006). Potent modulation of the voltage-gated sodium channel Nav1.7 by OD1, a toxin from the scorpion Odonthobuthus doriae.Mol. Pharmacol.70405–414. 10.1124/mol.106.022970
88
McDonoughS. I.LampeR. A.KeithR. A.BeanB. P. (1997). Voltage-dependent inhibition of N- and P-type calcium channels by the peptide toxin omega-grammotoxin-SIA.Mol. Pharmacol.521095–1104. 10.1124/mol.52.6.1095
89
McEneryM. W.SnowmanA. M.SharpA. H.AdamsM. E.SnyderS. H. (1991). Purified omega-conotoxin GVIA receptor of rat brain resembles a dihydropyridine-sensitive L-type calcium channel.Proc. Natl. Acad. Sci. U.S.A.8811095–11099. 10.1243/09544062JMES1490
90
McQueenC. (2017). Comprehensive Toxicology, 3rd Edn. Amsterdam: Elsevier Science.
91
MiddletonR. E.WarrenV. A.KrausR. L.HwangJ. C.LiuC. J.DaiG.et al (2002). Two tarantula peptides inhibit activation of multiple sodium channels.Biochemistry4114734–14747. 10.1021/bi026546a
92
MiljanichG. (2004). Ziconotide: neuronal calcium channel blocker for treating severe chronic pain.Curr. Med. Chem.113029–3040. 10.2174/0929867043363884
93
MinassianN. A.GibbsA.ShihA. Y.LiuY.NeffR. A.SuttonS. W.et al (2013). Analysis of the structural and molecular basis of voltage-sensitive sodium channel inhibition by the spider toxin huwentoxin-IV (μ-TRTX-Hh2a).J. Biol. Chem.28822707–22720. 10.1074/jbc.M113.461392
94
MintzI. M.VenemaV. J.SwiderekK. M.LeeT. D.BeanB. P.AdamsM. E. (1992). P-type calcium channels blocked by the spider toxin ω-Aga-IVA.Nature355827–829. 10.1038/355827a0
95
MoranY.GordonD.GurevitzM. (2009). Sea anemone toxins affecting voltage-gated sodium channels – molecular and evolutionary features.Toxicon541089–1101. 10.1016/j.toxicon.2009.02.028
96
MouhatS.VisanV.AnanthakrishnanS.WulffH.AndreottiN.GrissmerS.et al (2005). K(+) channel types targeted by synthetic OSK1, a toxin from Orthochirus scrobiculosus scorpion venom.Biochem. J.38595–104. 10.1042/BJ20041379
97
MurrayJ. K.LiguttiJ.LiuD.ZouA.PoppeL.LiH.et al (2015). Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the Na(V)1.7 sodium channel.J. Med. Chem.582299–2314. 10.1021/jm501765v
98
NajetS.DelavarS.ImenC.SaoussenM.HafedhM.LamiaB.et al (2008). Hemitoxin, the first potassium channel toxin from the venom of the Iranian scorpion Hemiscorpius lepturus.FEBS J.2754641–4650. 10.1111/j.1742-4658.2008.06607.x
99
NewcombR.SzokeB.PalmaA.WangG.ChenX. H.HopkinsW.et al (1998). Selective peptide antagonist of the class E calcium channel from the venom of the tarantula Hysterocrates gigas.Biochemistry3715353–15362. 10.1021/bi981255g
100
NovelloJ. C.ArantesE. C.VarandaW. A.OliveiraB.GiglioJ. R.MarangoniS. (1999). TsTX-IV, a short chain four-disulfide-bridged neurotoxin from Tityus serrulatus venom which acts on Ca2+-activated K+ channels.Toxicon37651–660. 10.1016/S0041-0101(98)00206-2
101
OhkuboT.YamazakiJ.KitamuraK. (2010). Tarantula Toxin ProTx-I differentiates between human t-type voltage-gated Ca2+ channels Cav3.1 and Cav3.2.J. Pharmacol. Sci.112452–458. 10.1254/jphs.09356FP
102
OliveiraJ. S.RedaelliE.ZaharenkoA. J.CassuliniR. R.KonnoK.PimentaD. C.et al (2004). Binding specificity of sea anemone toxins to Nav 1.1-1.6 sodium channels. Unexpected contributions from differences in the IV/S3-S4 outer loop.J. Biol. Chem.27933323–33335. 10.1074/jbc.M404344200
103
OliveraB. M.CruzL. J.de SantosV.LeCheminantG. W.GriffinD.ZeikusR.et al (1987). Neuronal calcium channel antagonists. Discrimination between calcium channel subtypes using omega-conotoxin from Conus magus venom.Biochemistry262086–2090. 10.1021/bi00382a004
104
OliveraB. M.GrayW. R.ZeikusR.McIntoshJ. M.VargaJ.RivierJ.et al (1985). Peptide neurotoxins from fish-hunting cone snails.Science2301338–1343. 10.1126/science.4071055
105
OliveraB. M.McIntoshJ. M.CruzL. J.GrayW. R.LuqueF. A. (1984). Purification and sequence of a presynaptic peptide toxin from Conus geographus Venom.Biochemistry235087–5090. 10.1021/bi00317a001
106
OliveraB. M.MiljanichG. P.RamachandranJ.AdamsM. E. (1994). Calcium channel diversity and neurotransmitter release: the ω-Conotoxins and ω-Agatoxins.Annu. Rev. Biochem.63823–867. 10.1146/annurev.bi.63.070194.004135
107
OliveraB. M.RivierJ.ClarkC.RamiloC. A.CorpuzG. P.AbogadieF. C.et al (1990). Diversity of Conus neuropeptides.Science249257–263. 10.1126/science.2165278
108
OrtsD. J. B.PeigneurS.MadioB.CassoliJ. S.MontandonG. G.PimentaA. M. C.et al (2013). Biochemical and electrophysiological characterization of two sea anemone type 1 potassium toxins from a geographically distant population of Bunodosoma caissarum.Mar. Drugs11655–679. 10.3390/md11030655
109
PayandehJ.ScheuerT.ZhengN.CatterallW. A. (2011). The crystal structure of a voltage-gated sodium channel.Nature475353–358. 10.1038/nature10238
110
PedarzaniP.D’HoedtD.DoortyK. B.WadsworthJ. D. F.JosephJ. S.JeyaseelanK.et al (2002). Tamapin, a venom peptide from the Indian red scorpion (Mesobuthus tamulus) that targets small conductance Ca2+-activated K+channels and after hyperpolarization currents in central neurons.J. Biol. Chem.27746101–46109. 10.1074/jbc.M206465200
111
PengK.ShuQ.LiuZ.LiangS. (2002). Function and solution structure of huwentoxin-IV, a potent neuronal tetrodotoxin (TTX)-sensitive sodium channel antagonist from Chinese bird spider Selenocosmia huwena.J. Biol. Chem.27747564–47571. 10.1074/jbc.M204063200
112
PenningtonM. W.ByrnesM. E.ZaydenbergI.KhaytinI.De ChastonayJ.KrafteD. S.et al (1995). Chemical synthesis and characterization of ShK toxin: a potent potassium channel inhibitor from a sea anemone.Int. J. Pept. Protein Res.46354–358. 10.1111/j.1399-3011.1995.tb01068.x
113
PringosE.VignesM.MartinezJ.RollandV. (2011). Peptide neurotoxins that affect voltage-gated calcium channels: a close-up on ω-agatoxins.Toxins317–42. 10.3390/toxins3010017
114
PuccaM. B.CerniF. A.CordeiroF. A.PeigneurS.CunhaT. M.TytgatJ.et al (2016). Ts8 scorpion toxin inhibits the Kv4.2 channel and produces nociception in vivo.Toxicon119244–252. 10.1016/j.toxicon.2016.06.014
115
RagsdaleD. S.McPheeJ. C.ScheuerT.CatterallW. A. (1996). Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.Proc. Natl. Acad. Sci. U.S.A.939270–9275. 10.1073/pnas.93.17.9270
116
RahnamaS.DeuisJ. R.CardosoF. C.RamanujamV.LewisR. J.RashL. D.et al (2017). The structure, dynamics and selectivity profile of a NaV 1.7 potency-optimised huwentoxin-IV variant.PLoS One12:e0173551. 10.1371/journal.pone.0173551
117
RauerH.LaniganM. D.PenningtonM. W.AiyarJ.GhanshaniS.CahalanM. D.et al (2000). Structure-guided transformation of charybdotoxin yields an analog that selectively targets Ca2+-activated over voltage-gated K+ channels.J. Biol. Chem.2751201–1208. 10.1074/jbc.275.2.1201
118
RedaelliE.CassuliniR. R.SilvaD. F.ClementH.SchiavonE.ZamudioF. Z.et al (2010). Target promiscuity and heterogeneous effects of tarantula venom peptides affecting Na+ and K+ ion channels.J. Biol. Chem.2854130–4142. 10.1074/jbc.M109.054718
119
RevellJ. D.LundP. E.LinleyJ. E.MetcalfeJ.BurmeisterN.SridharanS.et al (2013). Potency optimization of Huwentoxin-IV on hNav1.7: a neurotoxin TTX-S sodium-channel antagonist from the venom of the Chinese bird-eating spider Selenocosmia huwena.Peptides4440–46. 10.1016/j.peptides.2013.03.011
120
RobertsonB.OwenD. G. (1993). Pharmacology of a cloned potassium channel from mouse brain (MK-1) expressed in CHO cells: effects of blockers and an “inactivation peptide”.Br. J. Pharmacol.109725–735. 10.1111/j.1476-5381.1993.tb13634.x
121
Romi-LebrunR.LebrunB.Martin-EauclaireM. F.IshiguroM.EscoubasP.WuF. Q.et al (1997). Purification, characterization, and synthesis of three novel toxins from the Chinese scorpion Buthus martensi, which act on K+ channels.Biochemistry3613473–13482. 10.1021/bi971044w
122
RongM.ChenJ.TaoH.WuY.JiangP.LuM.et al (2011). Molecular basis of the tarantula toxin jingzhaotoxin-III ( -TRTX-Cj1 ) interacting with voltage sensors in sodium channel subtype Nav1.5.FASEB J.253177–3185. 10.1096/fj.10-178848
123
RyadhK.KamelM.MarcelC.HervéD.RazikaO.Marie-FranceM.et al (2018). Chemical synthesis and characterization of maurotoxin, a short scorpion toxin with four disulfide bridges that acts on K+ channels.Eur. J. Biochem.242491–498. 10.1111/j.1432-1033.1996.0491r.x
124
SanguinettiM. C.JohnsonJ. H.HammerlandL. G.KelbaughP. R.VolkmannR. A.SaccomanoN. A.et al (1997). Heteropodatoxins: peptides isolated from spider venom that block Kv4.2 potassium channels.Mol. Pharmacol.51491–498.
125
SarrahM.AmorM.GuillaumeS.ZiadF.TimoteoO.HervéR.et al (2003). Synthesis and characterization of Pi4, a scorpion toxin from Pandinus imperator that acts on K+ channels.Eur. J. Biochem.2703583–3592. 10.1046/j.1432-1033.2003.03743.x
126
SchmalhoferW. A.CalhounJ.BurrowsR.BaileyT.KohlerM. G.WeinglassA. B.et al (2008). ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors.Mol. Pharmacol.741476–1484. 10.1124/mol.108.047670
127
SidachS. S.MintzI. M. (2002). Kurtoxin, a gating modifier of neuronal high- and low-threshold Ca channels.J. Neurosci.222023–2034. 10.1523/JNEUROSCI.22-06-02023.2002
128
SilvaA. O.PeigneurS.DinizM. R. V.TytgatJ.BeirãoP. S. L. (2012). Inhibitory effect of the recombinant Phoneutria nigriventer Tx1 toxin on voltage-gated sodium channels.Biochimie942756–2763. 10.1016/j.biochi.2012.08.016
129
SwansonR.MarshallJ.SmithJ. S.WilliamsJ. B.BoyleM. B.FolanderK.et al (1990). Cloning and expression of cDNA and genomic clones encoding three delayed rectifier potassium channels in rat brain.Neuron4929–939. 10.1016/0896-6273(90)90146-7
130
SwartzK. J.MacKinnonR. (1995). An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula.Neuron15941–949. 10.1016/0896-6273(95)90184-1
131
TakacsZ.ToupsM.KolleweA.JohnsonE.CuelloL. G.DriessensG.et al (2009). A designer ligand specific for Kv1.3 channels from a scorpion neurotoxin-based library.Proc. Natl. Acad. Sci. U.S.A.10622211–22216. 10.1073/pnas.0910123106
132
TaoH.ChenJ. J.XiaoY. C.WuY. Y.SuH. B.LiD.et al (2013). Analysis of the interaction of tarantula toxin jingzhaotoxin-III (β-TRTX-Cj1α) with the voltage sensor of Kv2.1 uncovers the molecular basis for cross-activities on Kv2.1 and Nav1.5 channels.Biochemistry527439–7448. 10.1021/bi4006418
133
TaoH.ChenX.DengM.XiaoY.WuY.LiuZ.et al (2016). Interaction site for the inhibition of tarantula Jingzhaotoxin-XI on voltage-gated potassium channel Kv2.1.Toxicon1248–14. 10.1016/j.toxicon.2016.10.019
134
TarchaE. J.ChiV.Muñ;oz-ElíasE. J.BaileyD.LondonoL. M.UpadhyayS. K.et al (2012). Durable pharmacological responses from the peptide ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease.J. Pharmacol. Exp. Ther.342642–653. 10.1124/jpet.112.191890
135
TeichertR. W.RaghuramanS.MemonT.CoxJ. L.FoulkesT.RivierJ. E.et al (2012). Characterization of two neuronal subclasses through constellation pharmacology.Proc. Natl. Acad. Sci. U.S.A.10912758–12763. 10.1073/pnas.1209759109
136
UndheimE. A. B.MobliM.KingG. F. (2016). Toxin structures as evolutionary tools: using conserved 3D folds to study the evolution of rapidly evolving peptides.BioEssays38539–548. 10.1002/bies.201500165
137
UtkinY. N. (2015). Animal venom studies: current benefits and future developments.World J. Biol. Chem.628–33. 10.4331/wjbc.v6.i2.28
138
VandenbergJ. I.PerryM. D.PerrinM. J.MannS. A.KeY.HillA. P. (2012). hERG K+ channels: structure, function, and clinical significance.Physiol. Rev.921393–1478. 10.1152/physrev.00036.2011
139
VargaZ.Gurrola-BrionesG.PappF.Rodríguez de la VegaR. C.Pedraza-AlvaG.TajhyaR. B.et al (2012). Vm24, a natural immunosuppressive peptide, potently and selectively blocks Kv1.3 Potassium Channels of Human T Cells.Mol. Pharmacol.82372–382. 10.1124/mol.112.078006
140
VetterI.DekanZ.KnappO.AdamsD. J.AlewoodP. F.LewisR. J. (2012). Isolation, characterization and total regioselective synthesis of the novel μo-conotoxin MfVIA from Conus magnificus that targets voltage-gated sodium channels.Biochem. Pharmacol.84540–548. 10.1016/j.bcp.2012.05.008
141
WalshK. (2011). Targeting GIRK channels for the development of new therapeutic agents.Front. Pharmacol.2:64. 10.3389/fphar.2011.00064
142
WangG.LongC.LiuW.XuC.ZhangM.LiQ.et al (2018). Novel sodium channel inhibitor from leeches.Front. Pharmacol.9:186. 10.3389/fphar.2018.00186
143
WangJ.ShenB.GuoM.LouX.DuanY.ChengX. P.et al (2005). Blocking effect and crystal structure of natrin toxin, a cysteine-rich secretory protein from Naja atra venom that targets the BKCa channel.Biochemistry4410145–10152. 10.1021/bi050614m
144
WangX.UmetsuY.GaoB.OhkiS.ZhuS. (2015). Mesomartoxin, a new Kv1.2-selective scorpion toxin interacting with the channel selectivity filter.Biochem. Pharmacol.93232–239. 10.1016/j.bcp.2014.12.002
145
WhortonM. R.MacKinnonR. (2011). Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G-proteins, PIP(2) and sodium.Cell147199–208. 10.1016/j.cell.2011.07.046
146
WilliamsM. E.BrustP. F.FeldmanD. H.PatthiS.SimersonS.MaroufiA.et al (1992). Structure and functional expression of an ω-conotoxin-sensitive human N-type calcium channel.Science257389–395. 10.1126/science.1321501
147
WilsonM. J.YoshikamiD.AzamL.GajewiakJ.OliveraB. M.BulajG.et al (2011). -Conotoxins that differentially block sodium channels NaV1.1 through 1.8 identify those responsible for action potentials in sciatic nerve.Proc. Natl. Acad. Sci. U.S.A.10810302–10307. 10.1073/pnas.1107027108
148
WitcherD. R.De WaardM.LiuH.PragnellM.CampbellK. P. (1995). Association of native Ca2+ channel β subunits with the α1 subunit interaction domain.J. Biol. Chem.27018088–18093. 10.1074/jbc.270.30.18088
149
XiaoY.BinghamJ. P.ZhuW.MoczydlowskiE.LiangS.CumminsT. R. (2008). Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain II voltage sensor in the closed configuration.J. Biol. Chem.28327300–27313. 10.1074/jbc.M708447200
150
XiaoY.JacksonJ. O.LiangS.CumminsT. R. (2011). Common molecular determinants of tarantula huwentoxin-IV inhibition of Na+ channel voltage sensors in domains II and IV.J. Biol. Chem.28627301–27310. 10.1074/jbc.M111.246876
151
YanL.AdamsM. E. (2000). The spider toxin ω-Aga IIIA defines a high affinity site neuronal high voltage-activated calcium channels.J. Biol. Chem.27521309–21316. 10.1074/jbc.M000212200
152
YanL.HerringtonJ.GoldbergE.DulskiP. M.BugianesiR. M.SlaughterR. S.et al (2005). <em>Stichodactyla helianthus</em> peptide, a pharmacological tool for studying Kv3.2 channels.Mol. Pharmacol.671513–1521. 10.1124/mol.105.011064
153
YangS.XiaoY.KangD.LiuJ.LiY.UndheimE. A. B.et al (2013). Discovery of a selective NaV1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models.Proc. Natl. Acad. Sci. U.S.A.11017534–17539. 10.1073/pnas.1306285110
154
YaoJ.ChenX.LiH.ZhouY.YaoL.WuG.et al (2005). BmP09, a “long chain” scorpion peptide blocker of BK channels.J. Biol. Chem.28014819–14828. 10.1074/jbc.M412735200
155
YellenG. (2002). The voltage-gated potassium channels and their relatives.Nature41935–42. 10.1038/nature00978
156
YuanC.LiaoZ.ZengX.DaiL.KuangF.LiangS. (2007). Jingzhaotoxin-XII, a gating modifier specific for Kv4.1 channels.Toxicon50646–652. 10.1016/j.toxicon.2007.05.009
157
ZaharenkoA. J.SchiavonE.FerreiraW. A.LecchiM.FreitasJ. C.De RichardsonM.et al (2012). Characterization of selectivity and pharmacophores of type 1 sea anemone toxins by screening seven Navsodium channel isoforms.Peptides34158–167. 10.1016/j.peptides.2011.07.008
158
ZengX.DengM.LinY.YuanC.PiJ.LiangS. (2007). Isolation and characterization of Jingzhaotoxin-V, a novel neurotoxin from the venom of the spider Chilobrachys jingzhao.Toxicon49388–399. 10.1016/j.toxicon.2006.10.012
159
ZerroukH.MansuelleP.BenslimaneA.RochatH.Martin-EauclaireM. F. (1993). Characterization of a new leiurotoxin I-like scorpion toxin. PO5from Androctonus mauretanicus mauretanicus.FEBS Lett.320189–192. 10.1016/0014-5793(93)80583-G
160
ZhangM. M.WilsonM. J.AzamL.GajewiakJ.RivierJ. E.BulajG.et al (2013). Co-expression of NaVβ subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking μ-conotoxins.Br. J. Pharmacol.1681597–1610. 10.1111/bph.12051
161
ZhuS.PeigneurS.GaoB.LuX.CaoC.TytgatJ. (2012). Evolutionary diversification of Mesobuthus α-scorpion toxins affecting sodium channels.Mol. Cell. Proteomics11:M111.012054. 10.1074/mcp.M111.012054
162
ZornS.LeipoldE.HanselA.BulajG.OliveraB. M.TerlauH.et al (2006). The μO-conotoxin MrVIA inhibits voltage-gated sodium channels by associating with domain-3.FEBS Lett.5801360–1364. 10.1016/j.febslet.2006.01.057
Summary
Keywords
ion channel, venom, toxin peptides, animal toxin, ion channel pharmacology
Citation
Bajaj S and Han J (2019) Venom-Derived Peptide Modulators of Cation-Selective Channels: Friend, Foe or Frenemy. Front. Pharmacol. 10:58. doi: 10.3389/fphar.2019.00058
Received
16 June 2018
Accepted
18 January 2019
Published
26 February 2019
Volume
10 - 2019
Edited by
Alexander A. Vassilevski, Institute of Bioorganic Chemistry (RAS), Russia
Reviewed by
Steve Peigneur, KU Leuven, Belgium; José Javier López Barba, Universidad de Extremadura, Spain; Christian Legros, Université d’Angers, France
Updates
Copyright
© 2019 Bajaj and Han.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Saumya Bajaj, saumya.bajaj@ntu.edu.sg
†These authors have contributed equally to this work
This article was submitted to Pharmacology of Ion Channels and Channelopathies, a section of the journal Frontiers in Pharmacology
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.