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Block of Voltage-Gated Calcium Channels by Peptide Toxins Emmanuel Bourinet, Gerald Zamponi

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View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Archive Ouverte en Sciences de l'Information et de la Communication Block of voltage-gated calcium channels by peptide toxins Emmanuel Bourinet, Gerald Zamponi To cite this version: Emmanuel Bourinet, Gerald Zamponi. Block of voltage-gated calcium channels by peptide toxins. Neuropharmacology, Elsevier, 2016, 10.1016/j.neuropharm.2016.10.016. hal-02356298 HAL Id: hal-02356298 https://hal.archives-ouvertes.fr/hal-02356298 Submitted on 8 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Invited review Block of voltage-gated calcium channels by peptide toxins Emmanuel Bourinet, Gerald Zamponi To cite this version: Emmanuel Bourinet, Gerald Zamponi. Invited review Block of voltage-gated calcium channels by pep- tide toxins. Neuropharmacology, Elsevier, 2016, 10.1016/j.neuropharm.2016.10.016. hal-02356298 HAL Id: hal-02356298 https://hal.archives-ouvertes.fr/hal-02356298 Submitted on 8 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Neuropharmacology xxx (2016) 1e7 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Invited review Block of voltage-gated calcium channels by peptide toxins * Emmanuel Bourinet a, Gerald W. Zamponi b, a Institute for Functional Genomics, CNRS UMR5203, INSERM U1191, University of Montpellier, LABEX ICST, Montpellier, France b Department of Physiology and Pharmacology, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada article info abstract Article history: Venoms from various predatory species, such as fish hunting molluscs scorpions, snakes and arachnids Received 8 September 2016 contain a large spectrum of toxins that include blockers of voltage-gated calcium channels. These peptide Received in revised form blockers act by two principal manners - physical occlusion of the pore and prevention of activation 14 October 2016 gating. Many of the calcium channel-blocking peptides have evolved to tightly occupy their binding Accepted 15 October 2016 pocket on the principal pore forming subunit of the channel, often rendering block poorly reversible. Available online xxx Moreover, several of the best characterized blocking peptides have developed a high degree of channel subtype selectivity. Here we give an overview of different types of calcium channel-blocking toxins, their Keywords: fi Calcium channels mechanism of action, channel subtype speci city, and potential use as therapeutic agents. © Conotoxin 2016 Elsevier Ltd. All rights reserved. Agatoxin Protoxin Spiders Venom Pain Contents 1. Overview of voltage-gated calcium channels . .................................... 00 2. u-conotoxins . .. ................................................. 00 3. u-Agatoxins . ................................................. 00 4. Other toxins from spiders and scorpions . .................................... 00 5. Calcium channel blocking toxins from snakes . .................................... 00 6. How useful are calcium channel peptide toxins as therapeutics? . ..................... 00 Acknowledgments . ....................... 00 References................................................................. ................................ ....................... 00 1. Overview of voltage-gated calcium channels different types of Cav subunits, the principal pore forming subunit that forms the core of the calcium permeable ion channel (Simms Voltage-gated calcium channels are the major source of and Zamponi, 2014). They have been grouped into three major depolarization-evoked calcium entry into excitable cells of brain, classes (Cav1, Cav2 and Cav3) which in turn correspond to different heart, and muscle (Zamponi et al., 2015). This in turn supports types of calcium currents that have been identified in native tissues many critical physiological functions that range from muscle (for review, see Simms and Zamponi, 2014). The Cav1 family en- contraction, to the release of neurotransmitters and calcium- codes four different types of L-type channels. Among the Cav2 dependent gene transcription, among many others. The mamma- family, Cav2.1, Cav2.2 and Cav2.3 correspond, respectively, to P/Q- lian genome encodes as many as ten different genes that lead to type, N-type and R-type currents. The Cav3 family represents three different types of T-type calcium channels (also known as low-voltage activated channels due to their hyperpolarized voltage * Corresponding author. range of activation) (Catterall et al., 2005). Members of the Cav3 E-mail address: [email protected] (G.W. Zamponi). family are thought to be monomers whereas Cav1 and Cav2 http://dx.doi.org/10.1016/ j.neuropharm.2016.10.016 0028-3908 Please cite this article in press as: Bourinet, E., Zamponi, G.W., Block of voltage-gated calcium channels by peptide toxins, Neuropharmacology (2016), http://dx.doi.org/10.1016/j.neuropharm.2016.10.016 2 E. Bourinet, G.W. Zamponi / Neuropharmacology xxx (2016) 1e7 channels are multimeric complexes that also include a cytoplasmic Feng et al., 2003). Structure-function analysis based on chimeric Cavb and an extracellular Cava2d subunit (Simms and Zamponi, calcium channel constructs has revealed that GVIA interacts with 2014; Catterall et al., 2005). These ancillary subunits serve pri- the outer vestibule of the pore comprised of the extracellular marily to regulate calcium channel trafficking and function, but domain III S5eS6 (p-loop) region (Ellinor et al., 1994). Moreover, have also been shown to alter the pharmacological characteristics mutations in this region (especially a Glycine residue at position of the channels (Dolphin, 2016). All Cav subunits share a common 1326) have been shown to affect not only the blocking rate con- transmembrane topology of four homologous transmembrane do- stant, but also to have the capability to render the block reversible mains that each contain six membrane spanning helices plus a (Feng et al., 2001). These data fit with a structural homology model reentrant p-loop motif that forms the pore of the channel and of Cav2.2 based on the structure of bacterial sodium channels imparts calcium selectivity (Catterall et al., 2005). The fourth (Lewis et al., 2012). This picture is likely to be refined in light of the transmembrane helix in each domain contains a positively charged recent structural data of the Cav1.1 channel in complex with a amino acid residue in every third position and forms the voltage Cava2d subunit that is docked near the top of the channel pore (Wu sensor of the channel (Catterall, 2010). The major domains are et al., 2016). Such structural information may offer some mecha- connected by large cytoplasmic regions, in addition to being nistic insights into why the Cava2d subunit affects blocking and flanked by intracellular N- and C-terminal regions. The domain I-II unblocking rate constants for certain types of u-conotoxins (Mould linker is the locus for Cavb subunit interactions (Pragnell et al., et al., 2004). The venom of Conus geographus also contains other 1994). The recent breakthrough resolution of the Cav1.1 channel related u-conotoxins, such as GVIB, GVIC, GVIIA, and GVIIA, how- structure at a nearly atomic level brings us a step closer to the ever they are not as well characterized at the electrophysiological understanding of the interface between the Cav subunit and level as GVIA (Olivera et al., 1994). ancillary subunits (Wu et al., 2015, 2016). Notably these studies A number of calcium channel blocking peptides have been iso- revealed that Cava2d has a docking site formed by extracellular lated from the venom of Conus magus, another fish hunting snail. segments of domains I, II, and III, all organized with other extra- This includes u-conotoxins MVIIA, MVIIB, MVIIC, and MVIID cellular loops into a dome structure above the selectivity filter. (Hillyard, 1992; Olivera et al., 1994), which for the most part pref- Whether this organization is common to other Cav subtypes re- erentially target Cav2.2 channels (Olivera et al., 1985; Monje et al., mains to be determined. 1993; Fox, 1995). However, MVIIC also blocks Cav2.1 calcium The Cav subunit is the target for pharmacological agents that channels and its blocking effects are reversible (Woppmann et al., block (and in some cases enhance) calcium channel activity 1994; Grantham et al., 1994), underscoring the point that small (Zamponi et al., 2015). This is relevant in the context of therapeu-
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