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Neurobiology and Therapeutic Utility of Neurotoxins Targeting Postsynaptic

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Neurobiology and Therapeutic Utility of Neurotoxins Targeting Postsynaptic REVIEWS Drug Discovery Today Volume 24, Number 10 October 2019 Teaser This review presents the state-of-the-art for biological toxins targeting postsynaptic mechanisms of neurotransmission at the neuromuscular junction. It discusses emerging evidence for the therapeutic use of these biomolecules in the treatment of neuromuscular transmission disorders. Reviews Neurobiology and therapeutic utility KEYNOTE REVIEW of neurotoxins targeting postsynaptic mechanisms of neuromuscular transmission 1 2 3 Naira Ayvazyan is a Professor Naira M. Ayvazyan , Valerie B. O’Leary , J. Oliver Dolly and and the Head of the Orbeli 3,4,5 Institute of Physiology. She obtained her PhD in biophysics Saak V. Ovsepian from Yerevan State University. Her research interests cover 1 toxicology,membrane biophysics, Orbeli Institute of Physiology, National Academy of Sciences of the Republic of Armenia, Yerevan, Armenia 2 oxidative stress, and artificial Department of Medical Genetics, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Praha 10, supramolecular structures. She is Czech Republic a member of the Third Level 3 Education Board of Yerevan State University and serves as Dean of International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland 4 the Faculty of Neurophysiology and Toxicology at the International The National Institute of Mental Health, Topolová 748, Klecany, Czech Republic Scientific and Educational Centre of the National Academy of 5 Sciences ofArmenia. She is the Vice-President of the Pan-Armenian Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Ruská 87, 100 Biophysical Association and Treasurer of the Armenian IBRO 00, Praha 10, Czech Republic Association. Valerie B. O’Leary is an Assistant Professor in the The neuromuscular junction (NMJ) is the principal site for the translation Department of Medical Genetics, ThirdFacultyofMedicine,Charles of motor neurochemical signals to muscle activity. Therefore, the release University, Prague. She obtained her PhD from University College and sensing machinery of acetylcholine (ACh) along with muscle Dublin, Ireland on gene expression during somatic contraction are two of the main targets of natural toxins and pathogens, embryogenesis. International postdoctoral experience was causing paralysis. Given pharmacology and medical advances, the active subsequently obtained in centers of excellence, such as Columbia University, and the Lerner Institute Cleveland Clinic, USA. Her ingredients of toxins that target postsynaptic mechanisms have become of publication record covers biological areas from Drosophila GTPases, insulin resistance, neuroscience to cellular stress, which major interest, showing promise as drug leads. Herein, we review key facets form the basis of her teaching platformfor trainee medicalstudents. Her focus of research is currently on the role of long noncoding of prevalent toxins modulating the mechanisms of ACh sensing and transcriptomics. J. Oliver Dolly is a Science generation of the postsynaptic response, with muscle contraction. We Foundation of Ireland Professor and Director of the International consider the correlation between their outstanding selectivity and potency Centre for Neurotherapeutics, Dublin City University. He plus effects on motor function, and discuss emerging data advocating their obtained B.Sc. and M.Sc. degrees in Biochemistry from the University usage for the development of therapies alleviating neuromuscular of Galway, and Ph.D. in dysfunction. Biochemistry from the University of Wales. After training in the USA, Dr Dolly was awarded a professorship at Imperial College London. His meritorious achievements have been recognized by the award of a DSc in 2002. Dr Dolly pioneered the purification and characterization of acetylcholine receptors, research on neurotransmitter release and + Introduction targeting by toxins, as well as characterization of K channels. His work has been recognized by numerous awards, and by an honorary The NMJ links spinal cord motor neurons to skeletal muscles via a specialized connection, where membership of the Royal Irish Academy. electrochemical nerve signals are transmitted into the contraction of striated muscles. This Saak Victor Ovsepian is a Professor and the Head of the process is enabled predominantly via the release of ACh, which activates postsynaptic receptors, Department of Experimental Neurobiology at the National driving muscle contraction [1]. Structurally, the NMJ comprises three key constituents: (i) Institute of Mental Health, Czech presynaptic nerve terminal; (ii) synaptic cleft; and (iii) postsynaptic receptive elements of the Republic. He is also an adjunct professor at Dublin City striated muscle (Fig. 1). The presynaptic motor nerve terminal represents the biogenesis site for University. Dr Ovsepian has studied philosophy, biology, and synaptic vesicles and their loading with ACh followed by priming for fusion with the presynaptic medicine, earning a PhD in 2+ membrane. Upon depolarization of nerve terminals, the influx of Ca via voltage-gated channels evolutionary neurobiology. This was followed by training in several elite universities in the USA and Europe in molecular biology, synaptic triggers a complex sequence of molecular events, driving fusion of synaptic vesicles with the physiology, and neurodegenerative disease. Dr Ovsepian worked as Director of Neuroimaging and Neurophysiology at ICNT, Dublin and DZNE, Munich. His current research focuses on molecular and cellular mechanisms of neurodegenerative and neuropsychiatric diseases. Corresponding authors: Ayvazyan, N.M. ([email protected]), Ovsepian, S.V. ([email protected]) 1359-6446/ã 2019 Elsevier Ltd. All rights reserved. 1968 www.drugdiscoverytoday.com https://doi.org/10.1016/j.drudis.2019.06.012 Drug Discovery Today Volume 24, Number 10 October 2019 REVIEWS consider research advances in the biology and medical translation (a) Axon terminal (b) of toxins that interfere with ACh activity within the synaptic cleft and at the postsynaptic aspect of NMJs. Such a systematic analysis will enhance understanding of basic mechanisms underlying their AP VGCC injurious effects and their promote potential utility to improve the MF Ca+2 management and treatment of neurological conditions related to EPP abnormalities of synaptic transmission in the periphery and cen- NMJ tral nervous systems. Synaptic (c) vesicles VGPC Reversible antagonists of postsynaptic nAChR: curare and curaremimetics VGSC + K+ Na ACH Thelargestand best-studiedtoxingrouptargetingnAChRattheNMJ KEYNOTE REVIEW ACHE is represented by the curare family, named after the plants of Central NACHR and South America, from which active ingredients were first Drug Discovery Today extracted. Curare toxins belong to the class of bisbenzylisoquinoline Reviews alkaloids, which is a collection of (400) natural products. Although FIGURE 1 bisbenzylisoquinoline alkaloids in general exhibit a variety of well- The neuromuscular junction (NMJ) as a site of transmission of neuronal characterized biological activities, little is known about the phar- electrochemical signals into muscle contraction. (a) Schematic of the neuromuscular synapse connecting axon terminal with a muscle fiber. The macological properties of other ‘curare-like’ alkaloids [17]. Tradi- arrival of action potentials (AP) to the nerve terminal activates voltage-gated tionally, three different groups of curare products have been calcium currents (VGCC), which triggers the release of acetylcholine (ACH) into distinguished: (i) tube or bamboo curare (so-named because of its the synaptic cleft of the NMJ. Binding of ACH to postsynaptic nicotinic ACH presence in bamboo tubes; known also as D-tubocurarine); (2) pot receptors (NACHR) activates transmembrane voltage-gated sodium and curare (so-named because of its storage in terracotta pots), includes potassium currents (VGSC and VGPC) leading to activation of end plate potentials (EPPs) with a muscle contraction. (b) Scanning electron microscopy protocurarine, protocurine, and protocuridine as main alkaloids, image of the NMJ. (c) High-power transmission electron microscopy image of ranging from highly toxic to moderately toxic and nontoxic, respec- the NMJ. Scale bars: 2 m (b) and 400 nm (c). Abbreviations: AT, axon terminal; m tively; and (3) calabash (packed by Amazonian hunters into hollow MF, muscle fiber. Adapted from [195] (with permission) and www.anatomybox. gourds) with the main toxin known as C-curarine I [18,19]. The com/neuromuscular-junction-tem. Courtesy of Dr. Wacker-Schröder (c). history of the discovery of these toxins has been reviewed elsewhere [20–22] and expedited the identification of the first transmitter, surface membrane and ACh release into the synaptic cleft. There- ACh, and one of its receptors, nAChR. From all known variants, in, small quantities of released ACh bind to receptors and activate tubocurarine from Chondrodendron tomentosum is the most potent elementary postsynaptic potentials, which then depolarize motor and best characterized, being widely used in clinical and veterinary end plates, causing regenerative excitation waves and contraction practices since the 1940s as a potent muscle relaxant (Fig. 2a,b). of muscle fibers [2–4]. This complex and multistep reaction is Similar to most biological toxins, the effects of curare and curare- followed by the rapid hydrolysis of released ACh by acetylcholin- mimetics involve a multistep process, entailing their entry into the esterase
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