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Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein ISBN: 978-0-12-804794-1 ISSN: 1876-1623 For information on all Academic Press publications visit our website at http://store.elsevier.com CONTRIBUTORS Helena M Abelaira Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, Santa Catarina, Brazil Rashmi K Ambasta Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi, India Adela Banciu Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania Daniel Dumitru Banciu Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania Xu Chen College of Life Sciences, Shaanxi Normal University, Xi’an, Shaanxi, PR China Jinke Cheng Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China Chantelle Fourie Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand Roman V Frolov Division of Biophysics, Department of Physics, University of Oulu, Oulun Yliopisto, Finland Yan-Lin Fu Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Lucy Goodman Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand Zuleide M Igna´cio Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, Santa Catarina, Brazil Niraj Kumar Jha Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi, India ix x Contributors Saurabh Kumar Jha Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi, India Dhiraj Kumar Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi, India Pravir Kumar Molecular Neuroscience and Functional Genomics Laboratory, Delhi Technological University (Formerly DCE), Delhi, India, and Department of Neurology, Adjunct faculty, Tufts University School of Medicine, Boston, Massachusetts, USA Kevin Lee Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand Beulah Leitch Department of Anatomy, University of Otago, Dunedin, New Zealand Johanna M Montgomery Department of Physiology, Centre for Brain Research, University of Auckland, Auckland, New Zealand Ting-Wei Mu Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Yitao Qi College of Life Sciences, Shaanxi Normal University, Xi’an, Shaanxi, PR China Joa˜o Quevedo Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, Santa Catarina, Brazil; Center for Translational Psychiatry; Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, Medical School, and Neuroscience Graduate Program, Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, Texas, USA Beatrice Mihaela Radu Department of Neurological and Movement Sciences, Section of Anatomy and Histology, University of Verona, Verona, Italy, and Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Bucharest, Romania Mihai Radu Department of Neurological and Movement Sciences, Section of Anatomy and Histology, University of Verona, Verona, Italy, and Department of Life and Environmental Physics, ‘Horia Hulubei’ National Institute for Physics and Nuclear Engineering, Magurele, Romania Gislaine Z Reus Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, Santa Catarina, Brazil Contributors xi Ana Lu´cia S Rodrigues Laboratory of Neurobiology of Depression, Department of Biochemistry, Center of Biological Sciences, Federal University of Santa Catarina, Floriano´polis, Santa Catarina, Brazil Susan Schenk School of Psychology, Victoria University, Wellington, New Zealand Gerald Seifert Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany Christian Steinhaăuser Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany Stephanie E Titus Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA Talita Tuon Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciuma, Santa Catarina, Brazil Ya-Juan Wang Center for Proteomics and Bioinformatics and Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Matti Weckstr€ omw Division of Biophysics, Department of Physics, University of Oulu, Oulun Yliopisto, Finland Johannes Weller Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany Hongmei Wu College of Life Sciences, Shaanxi Normal University, Xi’an, Shaanxi, PR China w Matti Weckstr€ om has died PREFACE Ion channels are pore-forming membrane proteins expressed in almost all cell types These proteins trigger electrical signaling throughout the body by gating the flow of ions across the cell membrane Two characteristic features of ion channels distinguish them from other types of ion transporter proteins First, this is the very high rate of ion transport through the channel compared to other transporter proteins (often 106 ions per second or greater) and second, ions pass through channels down their electrochemical gradient without the participation of metabolic energy The sequencing of the human genome has identified more than 400 putative ion channels However, only a fraction of these theoretically identified channels have been cloned and functionally characterized The widespread tissue distribution of ion channels, along with the multiple physiological consequences of their opening and closing, makes targeting of ion channels very promising targets for development of therapeutics The potential validation of ion channels as drug targets provides an enormous market opportunity for their reemergence as key targets in drug discovery However, to realize the great potential of this target class, an understanding of the validation of these targets as well as development of suitable screening technologies that reflect the complexity of ion channel structure and function remains key drivers for exploitation of this opportunity In spite of some important drugs targeting ion channels which are today in clinical use, as a class, ion channels remain underexploited in drug discovery Furthermore, many existing drugs are poorly selective with significant toxicities or suboptimal efficacy This thematic volume of the Advances in Protein Chemistry and Structural Biology is dedicated to ion channels as therapeutic targets and more specifically as promising treatment targets in neurological and psychiatric disorders Chapter in this volume summarizes current advances about the protein biogenesis process of the Cys-loop receptors Operating on individual biogenesis steps influences the receptor cell surface level; thus, manipulating the proteostasis network components can regulate the function of the receptors, representing an emerging therapeutic strategy for corresponding channelopathies Chapter proposes for the first time a novel conceptual framework binding together transient receptor potential (TRP) channels, voltage-gated sodium channels (Nav), xiii xiv Preface and voltage-gated calcium channels (Cav) Authors propose a “flowexcitation model” that takes into account the inputs mediated by TRP and other similar channels, the outputs invariably provided by Cav channels, and the regenerative transmission of signals in the neural networks, for which Nav channels are responsible This framework is used to examine the function, structure, and pharmacology of these channel classes both at cellular and whole-body physiological level Building on that basis, the pathologies arising from the direct or indirect malfunction of the channels are discussed The numerous pharmacological interventions affecting these channels are also described Part of those are well-established treatments, like treatment of hypertension or some forms of epilepsy, but many others are deeply problematic due to poor drug specificity, ion channel diversity, and widespread expression of the channels in tissues other than those actually targeted Chapter reviews the potential role of ion channels in membrane physiology and brain homeostasis where ion channels and their associated factors have been characterized with their functional consequences in neurological diseases Furthermore, mechanistic role of perturbed ion channels identified in various neurodegenerative disorders is discussed Finally, ion channel modulators have been investigated for their therapeutic intervention in treating common neurodegenerative disorders Chapter is dedicated to acid-sensing ion channels (ASICs) which are important pharmacological targets being involved in a variety of pathophysiological processes affecting both the peripheral nervous system (e.g., peripheral pain, diabetic neuropathy) and the central nervous system (e.g., stroke, epilepsy, migraine, anxiety, fear, depression, neurodegenerative diseases) This review discusses the role played by ASICs in different pathologies and the pharmacological agents acting on ASICs that might represent promising drugs Perspectives and limitations in the use of ASICs antagonists and modulators as pharmaceutical agents are also discussed Chapter focuses on the glutamatergic system and its associated receptors that are implicated in the pathophysiology of major depressive disorder The N-methyl-D-aspartate (NMDA), a glutamate receptor, is a binding and/or modulation site for both classical antidepressants and new fast-acting antidepressants Thus, this review presents evidences describing the effect of antidepressants that modulate NMDA receptors and the mechanisms that contribute to the antidepressant response Chapter continues on the glutamatergic system Glutamate is the major neurotransmitter that mediates Preface xv excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction Their therapeutic potential has since declined due to inconsistent results in clinical trials However, recent advances in basic biomedical research significantly contribute to our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits has been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity Thus, these proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders Chapter is an experimental example of the role of the intercellular gap junction inwardly rectifying K+ (Kir) channels and two-pore domain K+ (K2P) channels in brain homeostasis maintained by astrocytes Authors combined functional and molecular analyses to clarify how low pH affects K+ channel function in astrocytes freshly isolated from the developing mouse hippocampus No evidence has been found for the presence of ASIC and transient receptor potential vanilloid receptors in hippocampal astrocytes However, the assembly of astrocytic K+ channels allows tolerating short, transient acidification, and glial Kir4.1 and K2P channels can be considered promising new targets in brain diseases accompanied by pH shifts Chapter in this volume discusses the ion channels modification by small ubiquitinlike modifier (SUMO) proteins and their role in neurological channelopathies, especially the determinants of the channels’ regulation SUMO proteins covalently conjugate lysine residues in a large number of target proteins and modify their functions SUMO modification (SUMOylation) has emerged as an important regulatory mechanism for protein stability, function, subcellular localization, and protein–protein interactions It is until recently that the physiological impacts of SUMOylation on the regulation of neuronal K+ channels have been investigated It is now clear that this ion channel modification is a key determinant in the function of K+ channels, and SUMOylation is implicated in a wide range of channelopathies, including epilepsy and sudden death Nonetheless, ion channels remain a relatively underexploited family of proteins for therapeutic interventions A number of recent advances in both xvi Preface technology and biomedical knowledge suggest that these proteins are promising targets for future therapeutic development Therefore, the aim of this volume is to promote further research in the structure, function, and regulation of different families of ion channels which would result in designing new efficient targeted drugs with significantly fewer adverse effects DR ROSSEN DONEV Biomed Consult Ltd United Kingdom CHAPTER ONE Proteostasis Maintenance of Cys-Loop Receptors Yan-Lin Fu*, Ya-Juan Wang†, Ting-Wei Mu*,1 * Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Center for Proteomics and Bioinformatics and Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Corresponding author: e-mail address: tingwei.mu@case.edu † Contents Introduction Folding, Assembly, and Degradation of Cys-Loop Receptors in the ER 2.1 Folding and Assembly of Cys-Loop Receptors 2.2 ERAD of the Cys-Loop Receptors Trafficking of Cys-Loop Receptors from ER to Golgi and to Plasma Membrane Protein Quality Control of Cys-Loop Receptors on the Plasma Membrane 4.1 Clustering 4.2 Endocytosis Other Regulations of Cys-Loop Receptors 5.1 Lipid Involvement in Trafficking and Clustering 5.2 Phosphorylation Signaling in the Biogenesis of the Receptors Disease and Therapy References 5 10 11 11 12 13 13 14 15 16 Abstract The Cys-loop receptors play prominent roles in the nervous system They include γaminobutyric acid type A receptors, nicotinic acetylcholine receptors, 5-hydroxytryptamine type-3 receptors, and glycine receptors Proteostasis represents an optimal state of the cellular proteome in normal physiology The proteostasis network regulates the folding, assembly, degradation, and trafficking of the Cys-loop receptors, ensuring their efficient functional cell surface expressions Here, we summarize current advances about the protein biogenesis process of the Cys-loop receptors Because operating on individual biogenesis steps influences the receptor cell surface level, manipulating the proteostasis network components can regulate the function of the receptors, representing an emerging therapeutic strategy for corresponding channelopathies Advances in Protein Chemistry and Structural Biology, Volume 103 ISSN 1876-1623 http://dx.doi.org/10.1016/bs.apcsb.2015.11.002 # 2016 Elsevier Inc All rights reserved Yan-Lin Fu et al INTRODUCTION The Cys-loop receptors, belonging to ligand-gated channels family, are activated by neurotransmitters, allowing ion flux through neuronal cell membrane to maintain the neuronal activity of central nervous system (CNS; Lester, Dibas, Dahan, Leite, & Dougherty, 2004) They include γ-aminobutyric acid type A receptors (GABAARs), nicotinic acetylcholine receptors (nAChRs), 5-hydroxytryptamine type-3 receptors (5-HT3Rs), and glycine receptors (GlyRs) As the Cys-loop receptors are composed of five homomeric or heteromeric subunits, they are also called pentameric ligandgated ion channels The bacterial GLIC and ELIC and the Caenorhabditis elegans GluCl are also in this superfamily The Cys-loop receptors have prominent roles in the nervous system As the most studied member, nAChRs are cation channels, permeable to Na+, K+, and Ca2+ upon activation They are responsible for synaptic transmission in the CNS, in autonomic ganglias, in the adrenal gland, and at neuromuscular junctions and other peripheral synapses The receptors are involved in diseases such as Alzheimer’s disease (AD), bipolar disease, and myasthenia gravis nAChRs located at different locations are composed of different sets of subunit subtypes α1, β1, γ, and δ subunits or α1, β1, δ, and ε subunits form muscle-type nAChRs at a 2:1:1:1 ratio, whereas α2–α10 and β2–β4 subunits compose the most neuronal-type receptors with (α4)3(β2)2, (α4)2(β2)3, or (α7)5 subtypes predominantly found in CNS and α3β4 subtypes in autonomic ganglion and adrenal gland (Gotti et al., 2009; Hogg, Raggenbass, & Bertrand, 2003; Mazzaferro et al., 2014; Palma, Bertrand, Binzoni, & Bertrand, 1996; Wu, Cheng, Jiang, Melcher, & Xu, 2015; Xiao & Kellar, 2004) 5-HT3Rs, the only inotropic receptor in serotonin receptor family, are also cation channels permeable to Na+, K+, and Ca2+ upon activation They are widely located at postsynaptic sites in hippocampus, cortex, substantia nigra, and brain stem They also exist in the presynaptic GABAergic nerve terminals in the amygdala and CA1 region of the hippocampus, presynaptic glutamatergic synapses, glial cell membranes in the medial nucleus of the solitary tract where they play a major role in regulating the release of neurotransmitters such as GABA, dopamine, glutamate (Connolly, 2008) They are involved in many clinical diseases such as drug addiction, cognitive function, schizophrenia, and satiety control Its antagonists are used to treat postinfectious irritable bowel syndrome and severe diarrhea-predominant 372 Wang, X.Q., 232–233 Wang, X.Y., 104t Wang, Y., 103–115, 213–214, 236–237, 301 Wang, Y.J., 2–16 Wang, Y.L., 122t Wang, Y.T., 53, 208 Wang, Y.-X., 214–215, 218–219 Wang, Z., 103–115, 104t, 212–213 Wang, Z.Z., 5–6 Ward, M.A., 223–224 Ward, S.E., 223–224 Wardlaw, J.M., 147 Warner, T.A., 231–232 Waroux, O., 312 Warren, S.T., 204–205, 229 Warth, R., 302–303, 304t Waryah, A.M., 13 Washizu, C., 121–125, 154–155 Wasserstrom, J.A., 45 Wasterlain, C.G., 204–205 Waszkielewicz, A.M., 60 Watabe, A.M., 215–216 Watanabe, A., 104t Watanabe, H., 69 Watanabe, M., 212–213 Waters, C.W., 116–117, 120t Watschinger, K., 72 Wauters, A., 184 Waxman, S.G., 40, 67, 104t, 117–118, 120t, 122t, 264–265, 284 Weber, M., 268 Webster, L.C., 215–216 Weckhuysen, S., 309–310 Weckstr€ om, M., 26–81 Weder, G., 141t Wegener, J.W., 51–52 Wegener, S., 229–230 Wegerich, Y., 227 Wei, C., 62 Wei, C.F., 297 Wei, I.H., 183 Wei, J., 225 Wei, W.L., 147–148 Wei, X., 151–152 Wei, Y.J., 150 Weight, F.F., 15 Weilinger, N.L., 99–100 Author Index Weinberg, R.J., 214–215, 220–221 Weiqiao, Z., 148–149 Weiss, B., 230–231 Weiss, D., 232–233 Weiss, L.A., 65 Weiss, N., 54–55 Weiss, S., 45–46 Weissert, R., 117–118, 120t Weissman, J.S., 4–5, Weitzner, D.S., 173 Weller, C.M., 64 Weller, J., 264–289 Wells, M.F., 229–230 Welsh, M.J., 141t, 149–151, 155, 282 Wemmie, J.A., 139, 141t, 152–155, 282 Wenker, I.C., 264–265, 283–284 Went, G.T., 173–174, 179 Wenthold, R.J., 205–208, 214–216, 218–219 Werdehausen, R., 39, 43–44, 64, 80, 102–103 Werneck, L.C., 104t Werner, P., 205–207 Wernig, M., 230–231 Wes, P.D., 31–32 Westbrook, G.L., 172–173 Westenbroek, R.E., 63–64, 296 Westmoreland, P.J., 155–156 Whalley, K., 223–224 Wheeler, D.G., 54 Whissell, P., 139 White, E., 45–46 White, H.S., 304t, 309–310 White, M.M., 13–14 White, T.W., 101–102 Whitehead, P.L., 229 Whiting, P.J., Whittle, N., 184 Whorton, M.R., 304t, 305–308, 312 Widdop, R.E., 122t Widmann, C., 287–289 Widmer, J., 185 Wiendl, H., 117–118, 120t Wigler, M., 228 Wihler, C., 222–223 Wilcox, K.S., 304t, 307–310 Wilders, R., 60–61 Wilhelmsson, U., 287–288 373 Author Index Wilkin, G.P., 80 Wilkinson, K.A., 296–297 Wille, A., 305–306 Willecke, K., 264–265 Willems, S., 60–61 Willemsen, M.H., 67 William Provance, D., 212–213 Williams, D.M., 285 Williams, J., 223–224 Williams, K., 228–229 Williams, T.C., 73 Wilson, N.R., 219–220 Wilson, S.P., 146 Winckler, B., 73, 104t Wing, K., 229 Winkler, P.A., 104t Winn, M.P., 62 Winter, C., 219–221 Winters, C.A., 212–213 Wischmeyer, E., 215 Wisden, W., 205–207 Wiseman, P.W., 208–210 Witte, M.M., 223–224 Wittmer, M., 74 Wlaz´, A., 183 Wlaz´, P., 183, 185 Wo´jcikowski, J., 179 Wolburg, H., 100–101 Wolf, M.E., 232 Wolf, P., 74 Wolfe, B.B., 236–237 Wollmuth, L.P., 205 Won, H., 229–230 Won, K., 229–230 Wong, C.W., 144 Wong, E.H.F., 179–180 Wong, H., 176, 229 Wong, H.K., 121–125, 154–155 Wong, J.M., 225–227, 236–237 Wong, L.W., 7–8 Wong, S.T., 56 Woo, D.H., 265, 286, 288–289 Wood, N.W., 303 Woodman, B., 154 Woodroffe, A., 228 Woodruff, G.N., 179–180 Woods, C.G., 104t Woodward, D.J., 153 Woodworth, M.A., 229–230 Worley, P.F., 29–30, 221–222 Wotton, D., 298–299 Wro´bel, A., 179, 183–185 Wu, A.L., Wu, D., 139 Wu, G., 115–116, 120t Wu, G.J., 177, 179 Wu, H., 139, 150–151, 157, 215, 218–219, 296–313 Wu, H.E., 177–178 Wu, H.Y., 225–227 Wu, J., 140, 176–177 Wu, L.G., 53–54 Wu, L.J., 115–116, 120t, 139, 204–205 Wu, L.W., 149–150 Wu, M., 122t Wu, N., 104t Wu, N.-P., 225 Wu, P.H., 225 Wu, S., 3–4 Wu, W.L., 144 Wu, W.N., 156–157, 264–265, 273, 282–283 Wu, X., 287 Wu, X.F., 100–101 Wu, Z.S., 2–3 Wunsch, A.M., 151, 155–156 Wuu, J., 122t, 229 Wycisk, K.A., 74 Wyczynski, A., 265, 268, 273, 277–279, 281, 284–286, 288–289 Wyss, R., 3–4 Wyszynski, M., 221–222 X Xi, J., 232 Xia, H., 210, 214–215, 221–222 Xia, J., 221–223 Xia, X., 300–301 Xia, Y.F., 223–224 Xia, Z.Y., 43–44 Xiao, B., 220–221 Xiao, C., 6–7, 15–16 Xiao, H., 11–12, 122t Xiao, W., 287–289 Xiaojie, L., 148–149 Xie, M., 265, 286, 288–289 374 Xiong, Q.J., 156–157, 264–265, 273, 282–283 Xiong, Z., 204–205 Xiong, Z.G., 141t, 143–144, 147–149, 153–154, 282 Xu, G., 265, 286, 288–289 Xu, H., 53, 122t, 141t, 149, 204–205 Xu, H.B., 225–227 Xu, H.E., 2–3 Xu, H.Y., 104t Xu, J., 104t, 116–117, 204–205, 225, 285–286 Xu, L., 139, 141t, 149, 180 Xu, N., 35 Xu, P., 41–42 Xu, R., 15 Xu, T.L., 139, 141t, 149 Xu, W., 217–219 Xu, X., 223–224 Xu, Y., 299–300 Xu, Y.J., 69 Xu, Z., 150–151 Xue, B., 173–174, 179 Xue, L.J., 122t Xun, Q., 143 Y Yamada, K.A., 306 Yamada, N., 234–235 Yamada, Y., 60 Yamagishi, T., 36–38, 41 Yamaguchi, S., 234–235 Yamaguchi, T., 10, 104t Yamaji, T., 184 Yamamoto, H., 208–210 Yamamoto, S., 103–115, 120t Yamanaka, A., 284 Yamanaka, K., 118–120, 120t Yamasaki-Mann, M., 104t Yamashiro, M., 175–176 Yamazawa, T., 104t Yamoah, E.N., 306–307 Yan Chiu, S., 305–306 Yan, G.X., 66 Yan, J., 151–152 Yan, J.Z., 183 Yan, L.Y., 122t Yan, S., 301 Author Index Yan, Z., 204–205 Yang, C., 176–177 Yang, C.R., 223–224 Yang, F., 12 Yang, H., 122t, 235 Yang, J., 118–120 Yang, J.J., 176–177 Yang, L., 287–289 Yang, P.S., 41–42, 52–53 Yang, T., 69 Yang, W., 41–42, 52–53 Yang, W.S., 144–145 Yang, Y., 149, 180, 304t, 309–310 Yang, Y.C., 121–125 Yang, Y.J., 122t Yang, Y.P., 153, 155 Yao, H.B., 104t Yao, H.H., 122t Yao, I., 220–221, 225–227 Yao, W.F., 177–178, 183 Yao, Y., 5–6 Yap, C.C., 73, 104t Yarishkin, O., 265, 286, 288–289 Yarov-Yarovoy, V., 26–27, 29, 31–32, 41–43 Yasuda, H., 298–300 Yasuda, R.P., 212–214, 236–237 Yates, J.R., 9, 15–16 Yazawa, M., 70 Ye, B., 69 Ye, C.P., 99–100 Ye, Q., 122t Yechikhov, S., 12 Yechikov, S., 104t Yeh, E.T.H., 296–302 Yekta, B.G., 180 Yereddi, N.R., 40–41 Yi, Z., 299–300 Yifeng, M., 148–149 Yingjun, G., 143 Yizhar, O., 235 Yong, Z.H., 104t Yongming, Q., 148–149 Yoo, J.W., 229, 303, 304t, 307–308, 310, 312 Yoon, B.E., 265 Yoon, J., 220–221 Yoosefi, A., 171 Author Index Yoshimura, K., 14 Yoshitomi, S., 104t Yoshiyama, Y., 118–120, 120t Young, A., 181 Yu, D., 55 Yu, D.F., 156–157, 264–265, 273, 282–283 Yu, E., 232–233 Yu, F., 141t Yu, F.H., 26–27, 29, 31–32, 41–43, 63–64, 296 Yu, G., 224–225 Yu, J., 182–183 Yu, T., 300–301 Yu, X.W., 156–157 Yu, Y., 141t Yuan, J., 287–289 Yuan, J.P., 29–30 Yuan, T., 173 Yuan, X., 10 Yudowski, G.A., 212–215 Yue, D.T., 41–42, 56 Yue, F., 299–300 Yuen, E.Y., 12–13 Yuki, D., 225–227 Yung, M., 229–230 Z Zacharoff, L., 154 Zadran, H., 223–224 Zagorska, A., 300–301 Zagzag, D., 156–157 Zahoor, M.Y., 13 Zahs, K.R., 284–285 Zaima, N., 225–227 Zajac, J.M., 141t Zaman, S.H., 208 Zamanian, J.L., 286 Zamanillo, D., 208 Zamorano, P.L., 204–205, 215, 218–219 Zamponi, G.W., 48, 49f, 50–56, 70, 73 Zang, Z.L., 150 Zarate, C.A., 171, 174–175, 178, 180 Zarb, C., 122t Zareba, W., 310 Zarrindast, M.R., 180 Zdebik, A.A., 285 Zeitz, C., 74 Zeng, F., 80 375 Zeng, S., 55 Zeng, W.Z., 139 Zeng, X.Y., 182–183 Zeric, T., 178 Zha, X.M., 138–139, 155–156, 282 Zhang, A.X., 225–227 Zhang, B., 104t Zhang, C.L., 304t Zhang, C.Y., 99–100 Zhang, G.Y., 139, 141t Zhang, H., 299–301 Zhang, L., 5–6, 15, 122t, 149, 218–219 Zhang, L.Y.J., 204–205, 236–237 Zhang, M., 69 Zhang, M.Y., 154–155 Zhang, P.W., 141t, 156–157 Zhang, S., 299–301 Zhang, S.J., 115–116, 120t Zhang, T., 182–183 Zhang, W., 68, 148–149, 213–214, 216 Zhang, X., 103–115, 122t, 212–213, 221, 265, 286, 288–289 Zhang, X.L., 182–183 Zhang, X.Y., 183, 225–227 Zhang, Y.Q., 115–116, 120t, 139, 149–151, 157, 225–227, 301 Zhang, Z., 299–300 Zhang, Z.D., 141t Zhang, Z.J., 177–178 Zhao, B., 103–115 Zhao, C.J., 10 Zhao, J., 68, 296–297 Zhao, M.G., 204–205 Zhao, P., 122t Zhao, Y., 103–115, 149 Zheleznyak, A., Zheng, C.Y., 215 Zheng, F., 34–35 Zheng, N., 214–215 Zhong, J., 51–52 Zhong, P., 225 Zhong, X., 177–178 Zhou, H.G., 149 Zhou, H.H., 225–227 Zhou, J., 306 Zhou, L., 225–227, 304t Zhou, M., 223–224, 265, 286, 288–289 376 Zhou, Q., 215–216 Zhou, S., 141t, 145–146 Zhou, W., 218–219 Zhou, Z.K., 122t Zhou, Z.Q., 176–177 Zhu, D.Y., 225–227 Zhu, J., 227 Zhu, X., 31–32 Zhu, X.M., 141t, 147–148 Zhu, Y., 229 Zhuang, X., 211–212 Zhuo, M., 229 Zianni, E., 122t Zieba, A., 183–185 Ziemann, A.E., 149–151, 155–156 Ziff, E.B., 207, 221–223 Zijlstra, F.J., 145 Zimmer, T., 74–75 Zimmerman, A.W., 228 Zimmerman, D.M., 223–224 Zimmermann, H., 99–100 Author Index Zimmermann, K., 68, 287–288 Zingman, L.V., 305–306 Ziogas, J., 57–58 Zipursky, S.L., 99 Zito, K., 182–183, 185 Zitzer, H., 220–221 Zlokovic, B.V., 100–101 Znojek, P., 183 Zon, L.I., 301 Zona, C., 118–120, 120t Zong, S., 54 Zou, Y., 298–301, 308 Zuberi, S.M., 303 Zuhlke, R.D., 56 Zukervar, P., 179 Zukin, R.S., 173–174, 223 Zuniga, E., 204–205 Zuniga, L., 304t Zuo, Y., 298–302, 308 Zuschratter, W., 219–221 Zygmunt, A.C., 45–46 SUBJECT INDEX Note: Page numbers followed by “f ” indicate figures, and “t” indicate tables A Absence epilepsy, 235–236 Acamprosate, 232–233 Acid-sensing ion channels (ASICs), 26–27, 121–125, 156–157 agonists, 140–143, 141t antagonists, 140–143, 141t biophysical properties multiple receptors, ion channels, pumps, and transporters, 139–140, 140f protons as neurotransmitters, 139 structural and conformational changes, 138–139 brain ischemia/stroke, 147–149, 148f diabetic foot, 146, 146f diabetic neuropathy, 143–145, 144f migraine, 151–152 modulators, 140–143, 141t neurodegenerative disorders Alzheimer’s disease, 153, 155 epilepsy, 149–151 Huntington’s disease, 154 multiple sclerosis, 152–154 Parkinson’s disease, 153–155 peripheral pain, 143, 144f, 145–146 psychiatric disorders, 155–156 Action potentials (APs), 26, 309–310 AD See Alzheimer’s disease (AD) Agrin, 12 Alpha-amino-3-hydroxy-5-methyl4-isoxazole-propionate (AMPA) receptors, 172 extrasynaptic glutamate receptors, 211–212 functional properties, 207 LTP and LTD, 207–210 mobility of, 213–214 nanodomains, 211–212 neurodegenerative diseases Alzheimer’s disease, 223–224 animal models, 236–237 ASD (see Autism spectrum disorders (ASD)) drug addiction, 231–233 epilepsy, 233–236 Huntington’s disease, 225 Parkinson’s disease, 223–225 PSD scaffolding proteins, 225–227 newly exocytosed receptors, 212–213 NMDAR-only “silent synapses”, 212–213 perisynaptic glutamate receptors, 211–212 postsynaptic density ABP/GRIP and PICK1, 221–223 MAGUKs, 215 PSD95 proteins, 216–217 SAP97, 217–219, 220f Shank proteins, 218f, 219–221 stargazin proteins, 216–217 recycling of, 214–215 subunit composition, 205–207 synaptic strength, 212–213 ALS See Amyotrophic lateral sclerosis (ALS) Alzheimer’s disease (AD), aberrant channels, 103–115 AMPA receptors, 223–224 ASICs ASIC1a channels, 153 CHF5074, 155 local brain ischemia, 153 excitotoxicity, 171 memantine, 177 Amantadine, 179 Amiloride migraine, 152 multiple sclerosis, 154 Parkinson’s disease, 154–155 peripheral pain, 143 psychiatric disorders, 156 seizures, 150–151 stroke, 148 1-Aminocyclopropanecarboxylic acid (ACPC), 181 377 378 2-Amino-7-phosphonoheptanoic acid (AP-7), 181–182 AMPA receptor-binding proteins (ABPs), 221–223 AMPA receptors See Alpha-amino-3hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors Amyloid precursor protein (APP), 103–115, 152–153, 225–227 Amyotrophic lateral sclerosis (ALS), 98–99, 118–120, 204–205 Antianginal drug, 44–46 Antiarrhythmic drug, 44–46 Antidepressants ACPC, 181 amantadine, 179 AP-7, 181–182 ascorbic acid, 186–187 CGP-37849, 180–181 eliprodil, 182 glycine modulators, 182–183 guanosine, 187 ketamine (see Ketamine) magnesium, 183–185 memantine, 177–179 MK-801, 179–180 Ro25-6981, 180 zinc, 183–185 Ascorbic acid, 186–187 ASD See Autism spectrum disorders (ASD) ASIC See Acid-sensing ion channels (ASICs) Astrocytes ASICs amiloride, 277, 278f ASIC1a and ASIC2, 277, 278f, 282 brain ion homeostasis, role in, 264 extracellular acidification, 264–265 intracellular acidification, 264–265 intracellular pH, regulation of, 264–265 Kir4.1 channels, 265 Ba2+, low pH elicited membrane currents, 274–275, 275f epilepsy, 284–285 Huntington’s disease, 285–286 multiorgan disorder, 285 multiple sclerosis, 286 pH sensitivity of, 273 TLE-HS patients, 285 Subject Index K2P channels glutamate, release pore for, 265 heteromeric channels, 265 KCNK1, KCNK2, KCNK10 mRNA expression, developmental regulation of, 281–282, 281f as pharmacological targets, 287–289 TASK1 and TASK3 mRNA, 279–281 TREK-1 channels, 265, 277–279, 280f, 286–287 TWIK-1, 286 materials and methods cell harvesting and single-cell RT-PCR, 268–271, 269t data analysis, 272 electrophysiological recordings, 267–268 freshly isolated cells, preparation of, 266 HEK-293 cell culture and transfection, 267 semiquantitative RT-PCR, brain tissue preparation, 271 slice preparation, 266 neurotransmitter uptake, 264 pathophysiological conditions, 264 pH sensitivity of, 273, 274f, 283–284 TRPV1, 264–265, 277, 278f, 282–283 voltage-activated K+ currents, 275–276, 275f Atrial standstill, 66 Atrioventricular node (AVN), 44, 52–53, 58–59 Autism spectrum disorders (ASD), 63–64 AMPA receptor modulators, FXS patients, 229 definition, 228 glutamate receptors, genetic changes in, 228 infantile autism, 228–229 pharmaceutical treatments for, 228–229 synaptic proteins, 229–231 B Ball and chain mechanism, 38–39, 50 BBB See Blood–brain barrier (BBB) BDNF See Brain-derived neurotrophic factor (BDNF) 379 Subject Index Benign familial neonatal–infantile seizures (BFNIS), 64–65 Benzamil, 121–125, 154–155 Benzothiazepines (BT), 51 Benzothiazoles (riluzole), 46 BFNIS See Benign familial neonatal–infantile seizures (BFNIS) Biological transducers, 28–29 Biotrafficking, 100–101 Bipolar disease, 2, 15–16 Bipolar disorder (BD), 57, 171, 178–179 Blood–brain barrier (BBB), 100–101, 145–146 Bothrops jararaca, 80 Brain-derived neurotrophic factor (BDNF) ketamine, 175 memantine, 178 Brefeldin A-inhibited GDP/GTP exchange factor (BIG2), 10 Brugada syndrome, 66–68, 70–71, 74, 76–77 C Caenorhabditis elegans, 2, 11 Calcitonin gene-related peptide (CGRP), 152 Calcium channel-associated transcript (CCAT), 51–52 Calcium channels, pharmacological therapy blockers and modulators, Cav2 channels, 59–60 L-type channel blockers, 57–59 nonspecific Cav channel inhibitors, 60 Calcium-dependent facilitation (CDF), 55–56 Calcium-dependent inactivation (CDI), 50 Calcium sensitivity mechanism, 41–42 cAMP response element-binding protein (CREB), 51–52 Captopril, 80 Carbamazepine, 46–47 Carboxamides (carbamazepine), 46 CCAT See Calcium channel-associated transcript (CCAT) Central nervous systems (CNS), 40 CGP-37849, 180–181 CGRP See Calcitonin gene-related peptide (CGRP) Chronic mild stress (CMS), 175 Clathrin, 12 CNS See Central nervous systems (CNS) Collybistin, 11–12 Cone snail, 80 Congenital sick sinus syndrome, 66 Congenital stationary night blindness type (CSNB2), 71 Conus magus, 80 Cortical spreading depression (CSD), 151–152 CREB See cAMP response elementbinding protein (CREB) Cyclic nucleotide-gated (CNG) channels, 26–27 Cys-loop receptors disease and therapy, 15–16 ERAD of, 8–10 folding and assembly assembly process, BiP, chaperones, ER retention signal, 5–6 Golgi and plasma membrane, 5–6 nAChR assembly, N-terminal signal, 7–8 pathogenic mutations, 6–7 RIC-3, high-resolution structures, 3–4 hydroxytryptamine type-3 receptors, 2–3 intersubunit assembly, 3–4 lipid involvement, trafficking and clustering, 13–14 nAChRs, neurotransmitters, phosphorylation signaling, 14–15 protein biogenesis pathway, 5f protein quality control, plasma membrane clustering, 11–12 endocytosis, 12–13 proteostasis maintenance, 4–5 receptor-mediated neuron activity, 4–5 structural characteristics, 4f trafficking, 10–11 γ-aminobutyric acid type A receptors, D Damage-associated pattern protein (DAMP), 287 Depression See Major depressive disorder (MDD) 380 Diabetic neuropathy, 143–145, 144f Diacylglycerol (DAG), 34–35 Dihydropyridines (DHPs), 51, 121–125 Dopaminergic (DA) neurons, 115–116 Dravet syndrome, 63–64 Drosophila melanogaster larvae, 45 Drug addiction, 231–233 E ECC See Excitation–contraction coupling (ECC) Effective refractory period (ERP), 44–45 Eiprodil, 182 Endoplasmic reticulum (ER), 4–5 Epilepsy AMPA receptors, 233–236 ASICs, 149–151 CGP-37849, 180–181 excitotoxicity, 171 and sudden death, SUMOylation (see Sudden unexplained death in epilepsy (SUDEP)) Episodic ataxia type (EA2), 72 ER-associated degradation (ERAD), 4–5 ERP See Effective refractory period (ERP) Etiological therapy, 76 Excitation–contraction coupling (ECC), 51 Experimental autoimmune encephalomyelitis (EAE), 152–154 F Familial episodic pain syndrome (FEPS1), 62 Familial hemiplegic migraine (FHM), 63–64, 72 Familial rectal pain syndrome, 67 Fatty acid derivatives (valproate), 46 FCD See Focal cortical dysplasia (FCD) FHM See Familial hemiplegic migraine (FHM) Flecainide, 76 Flow-of-excitation model channelopathies acquired channelopathies, 74–76 human and animal physiology, 61 treatment of, 76–77 TRP, 61–63 voltage-gated Na+ channels, 63–69 Subject Index electrical excitation, 26 neural circuits acetylcholine receptors, 30 AMPA and NMDA receptor channels, 29–30 biological organism, 27–28 calcium influx, 28–29 electromechanical system, 27–28 electroreceptors, 31 epilepsy spectrum disorders, 79 ethosuximide, 79 input excitatory cationic channels, 30–31 integrated artificial and biological systems, 28f L-type Cav channels, 31 Nav channels, 28–29 neuropathic disorders, 78–79 output channels, 30–31 pharmacological therapy, 77–78 ranolazine, 79 transducer, 27–28 TRP and Cav channels, 28–29 perspectives, 80–81 TRP channels activation and modulation mechanisms, 31–32 Drosophila photoreceptors, 31–32 regulation and activation mechanisms, 34–35 structure and structural varieties, 32–34 therapeutic potential, 35–36 voltage-gated Ca2+ channels Cav1 channels, 51–53 Cav2 channels, 53–54 Cav3 channels, 54–55 Cav currents, 47–48 pharmacological therapy, 57–60 regulation, 55–57 structure and function, 48–50 wide-ranging regulatory influences, 48 voltage-gated Na2+ channels inactivation, 38–40 isoforms and expression, 40 regulation, 40–42 sodium currents, 36–37 structure, 37–38 therapeutic targets, 42–47 381 Subject Index Flunarizine, 60 Fluspirilene, 60 Focal cortical dysplasia (FCD), 150 Forced swimming test (FST) ACPC, 181 AP-7, 181–182 eliprodil, 182 guanosine, 187 ketamine, 175 memantine, 177–178 Ro25-6981, 180 Fragile X syndrome (FXS), 229 Fructose derivatives (topiramate), 46 FST See Forced swimming test (FST) G Gabapentin, 59–60 Generalized epilepsy with febrile seizures plus type (GEFS+type 2), 63–64 Gephyrin, 11–12 Giant ankyrin-G, 13 Glutamate (Glu), 171, 188f astrocyte-neuronal cycle, 172 excitotoxicity, 171 glutamate–glutamine cycle, 172 iGluRs AMPA receptors (see Alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors) kainate receptors, 172 NMDA receptor (see N-methyl-Daspartate (NMDA) receptors) Krebs/tricarboxylic acid cycle, 172 mGluRs, 173 neurons, 171–172 pre- and postsynaptic proteins, 204–205, 206f tripartite synapse, 173 Glutamate receptor-interacting protein (GRIP), 221–223, 230–231 Glycine modulators, 182–183 Glycogen synthase kinase-3 (GSK-3), 176–177 GRIP See Glutamate receptor-interacting protein (GRIP) Guanosine, 187 H Hamilton Depression Rating Scale (HDRS), 178–179 HD See Huntington’s disease (HD) High voltage-activated (HVA) phenotype, 48–49 Hirudo medicinalis, 80 HOKPP See Hypokalemic periodic paralysis (HOKPP) Huntingtin-associated protein (HAP1), 12–13 Huntington’s disease (HD) aberrant channels, 116–117 AMPA receptor, 225 ASICs, 154 excitotoxicity, 171 Kir4.1 channels, 285–286 Hv1 proton channel, 115–116 Hydantoins (phenytoin), 46 Hyperkalemic periodic paralysis (HyperPP), 65 Hypokalemic periodic paralysis (HOKPP), 65, 69 I ICD See Intracellular loop domain (ICD) Idiopathic ventricular fibrillation type 1, 66 Interleukin-6 (IL-6), 177 Intracellular chloride channel (CLIC1), 103–115 Intracellular loop domain (ICD), Ion channels architecture of, 113f ASICs (see Acid-sensing ion channels (ASICs)) BBB, 100–101 gap junctional channels, 101–102 homeostasis, 101–102 intricacy, membrane physiology, 99 ion disturbance, 102–103 neurological diseases, 104t role, brain homeostasis, 99–100 Ionotropic glutamate receptors (iGluRs) AMPA receptors (see Alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors) kainate receptors, 172 382 Ionotropic glutamate receptors (iGluRs) (Continued ) NMDA receptors (see N-methyl-Daspartate (NMDA) receptors) Ischemic brain injury, 147–149, 148f Isolated cardiac conduction system disease (ICCSD), 66 J Juvenile myoclonic epilepsy (JME), 74 K Ketamine antidepressant effects of AMPA receptors, 175–176 mTOR, 176–177 oxidative stress and inflammation, 177 in preclinical animal studies, 175 in treatment-resistant MDD patients, 174–175 isomers of, 174 as monoanesthetic drug, 174 as venous anesthetic, 174 Kinesin superfamily motor protein (KIF5), 12–13 L Lambert–Eaton myasthenic syndrome, 74–75 Lamotrigine, 46–47 LAs See Local anesthetics (LAs) Leech, 80 Local anesthetics (LAs), 42–44 Long QT syndrome (LQTS), 66, 70 Long-term depression (LTD), 29–30, 207–210 Long-term potentiation (LTP), 207–210 Low voltage-activated (LVA) phenotype, 48–49 L-type Ca2+ channels (LTCCs), 115–116, 121–125 L-type channel blockers, 57–59 Lysosomal trafficking, 62 M Magnesium, 183–185 Major depressive disorder (MDD) glutamatergic system, 171, 188f Subject Index astrocyte-neuronal cycle, 172 excitotoxicity, 171 glutamate–glutamine cycle, 172 iGluRs, 172–173 Krebs/tricarboxylic acid cycle, 172 mGluRs, 173 neurons, 171–172 tripartite synapse, 173 monoamine deficiency hypothesis, 170–171 morbidity and mortality, 170 NMDA receptors, 189f ACPC, 181 amantadine, 179 AP-7, 181–182 ascorbic acid, 186–187 CGP-37849, 180–181 eliprodil, 182 glycine modulators, 182–183 guanosine, 187 ketamine (see Ketamine) magnesium, 183–185 memantine, 177–179 MK-801, 179–180 Ro25-6981, 180 zinc, 183–185 prevalence, 170 standard antidepressants, 170–171 Malignant hyperthermia susceptibility (MHS) syndrome, 69 Mammalian target of rapamycin (mTOR) ketamine, 176–177 memantine, 178 Ro25-6981, 180 Maternal care deprivation (MCD), 175 MDD See Major depressive disorder (MDD) Memantine, 177–179 ASD patients, 228–229 biological compounds, 122t Membrane associated guanylate kinases (MAGUKs), 215 Metabotropic glutamate receptors (mGluRs), 173 Mexiletine, 76 Migraine, 47 ASICs, 151–152 calcium ion channel aberrations, 102–103 383 Subject Index MK-801, 179–180 mTOR See Mammalian target of rapamycin (mTOR) Multiple sclerosis (MS) aberrant channels, 117–118 ASICs amiloride, 154 ASIC1a channels, 152–153 Kir4.1 channels, 286 Myasthenia gravis, N Nav channels, therapeutic targets antiarrhythmic and antianginal drugs, 44–46 local anesthetics, 43–44 neurological disordes, 46–47 N-ethylmaleimide-sensitive factor (NSF), 210 Neuregulins 1β (NRG1β), 13 Neurodegenerative disorders (NDDs) aberrant channels ALS, 118–120 Alzheimer’s disease, 103–115 defective channels and associated mechanisms, 120t Huntington’s disease, 116–117 ion channel-mediated pathogenesis, molecular mechanism of, 119f multiple sclerosis, 117–118 Parkinson’s disease, 115–116 Alzheimer’s disease ASICs, 153, 155 excitotoxicity, 171 memantine, 177 AMPA receptors (see Alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors) ASICs, Huntington’s disease, 154 excitotoxicity, Huntington’s disease, 171 ion channels architecture of, 113f BBB, 100–101 gap junctional channels, 101–102 homeostasis, 101–102 intricacy, membrane physiology, 99 ion disturbance, 102–103 neurological diseases, 104t role, brain homeostasis, 99–100 multiple sclerosis, ASICs, 152–154 Parkinson’s disease amantadine, 179 ASICs, 153–155 therapeutics approach ion channel modulators, 122t neurological channelopathies, 121–125 strategies, 121–125 Neurosteroids, 14–15 Nicotine, 15–16 N-methyl-D-aspartate (NMDA) receptors, 171, 173–174, 189f ACPC, 181 amantadine, 179 AP-7, 181–182 ascorbic acid, 186–187 CGP-37849, 180–181 eliprodil, 182 glycine modulators, 182–183 guanosine, 187 ketamine (see Ketamine) magnesium, 183–185 memantine, 177–179 MK-801, 179–180 Ro25-6981, 180 zinc, 183–185 O Onabotulinumtoxin, 152 Oxidative stress, 177 P Paeoniflorin, 155 Palmitoylation, 10 Paramyotonia congenita, 65 Paraneoplastic neurological disorders, 75 Parkinson’s disease (PD), 71, 74 aberrant channels, 115–116 amantadine, 179 AMPA receptors, 223–225 ASICs amiloride, 153–155 ASIC1, 153 ASIC2a, 153 paeoniflorin, 155 Paroxysmal extreme pain disorder (PEPD), 67 384 PD See Parkinson’s disease (PD) Perampanel, 235 Peripheral nervous systems (PNS), 40 Peripheral pain, 143, 144f, 145–146 Phenylalkylamines (PAA), 51 Phenytoin, 46–47 Phosphatidylethanolamine, 13–14 Phospholipase C (PLC), 34–35 Phospholipase C-related catalytically inactive protein (PRIP), 10 PNS See Peripheral nervous systems (PNS) Postsynaptic density (PSD) ABP/GRIP and PICK1, 221–223 MAGUKs, 215 PSD95 proteins, 216–217 SAP97, 217–219, 220f Shank proteins, 218f, 219–221 stargazin proteins, 216–217 Potassium-aggravated myotonia (PAM), 65 Potassium (K+) channels, 304t K2P1, 302–303 Kv1.5, 305–306 Kv2.1, 306 Kv1.1 and Kv1.2, 303–304 Kv7.1, Kv7.2, and Kv7.3, 306–307, 309–312, 311f Pregabalin, 59–60 Primary aldosteronism, seizures, and neurologic abnormalities (PASNA) syndrome, 71 Primary erythromelalgia (PE), 67 Protein interacting with C Kinase (PICK1), 221–223 Protein kinase A (PKA), 9–10, 41, 173–174 Protein tyrosine kinases (PTKs), 15 PSD See Postsynaptic density (PSD) PSD95 proteins, 216–217 Psychiatric disorders, ASICs, 155–156 Pyrimidine-2,4,6-triones, 121–125 Q Quantum dots (QDs), 213–214 R RACK See Receptor for activated c-kinase (RACK) Radixin, 12 Ranolazine, 45–46 Subject Index Rapsyn, 12 Rebound bursting, 54–55, 73 Receptor for activated c-kinase (RACK), 14–15 Rectification index (RI), 272 Resistance to inhibitors of acetylcholinesterase (RIC-3), Resurgent current, 39–40 Retigabine, 310–311 Riluzole, 45–47, 228–229 Rizatriptan, 152 Ro25-6981, 180 S SAN dysfunction and deafness syndrome (SANDD), 71 Sarcoplasmic reticulum (SR), 51 Severe myoclonic epilepsy of infancy (SMEI), 63–64 Shank proteins, 218f, 219–221 Alzheimer’s disease, 227 ASD-associated mutations, 229–231 Sinoatrial node (SAN), 40, 44 Spinocerebellar ataxia type (SCA6), 72 Stargazin proteins, 216–217 Substantia nigra pars compacta (SNc), 115–116 Sudden infant death syndrome, 66 Sudden unexplained death in epilepsy (SUDEP) neuronal ion channel genes, mutations in, 296 posttranslational modifications, 296–297 premature mortality, cause of, 296 SUMOylation, 312–313 Kv7 channels, hyper-SUMOylation of, 309–312, 311f Kv1.1 deficiency, 303 SENP2 deficiency, 308–309 SENP2 in vivo, role of, 308 SUMO-specific proteases (SENPs) catalytic activity, 299–300 hydrolase activity, 299–300 isopeptidase activity, 299–300 SENP1, 300–301 SENP2, 300–301, 308–309 SENP3 and SENP5, 300–301 SENP6 and SENP7, 300, 302 385 Subject Index SUMOylation, 296–297, 312–313 activating enzyme (E1), 298 conjugating enzyme (E2), 298–299 epilepsy and sudden death Kv7 channels, hyper-SUMOylation of, 309–312, 311f SENP2 in vivo, role of, 308 isoforms, 297–298 ligasing enzyme (E3), 298–299 and potassium ion channels, 304t K2P1, 302–303 Kv1.5, 305–306 Kv2.1, 306 Kv1.1 and Kv1.2, 303–304 Kv7.1, Kv7.2, and Kv7.3, 306–307 promyelocytic leukemia protein, 299 RanGAP1, 299 SENPs catalytic activity, 299–300 hydrolase activity, 299–300 isopeptidase activity, 299–300 SENP1, 300–301 SENP2, 300–301 SENP3 and SENP5, 300–301 SENP6 and SENP7, 300, 302 Superoxide dismutase (SOD1), 118–120 Surface trafficking, T Tandem of P-domains in a weakly inward rectifying K+ channel (TWIK-1), 265, 286 Tay–Sachs disease, 77 Temporal lobe epilepsy (TLE), 149–150 Temporal lobe epilepsy and hippocampal sclerosis (TLE-HS), 285 Tetrodotoxin (TTX), 36–37 Timothy syndrome (TS), 70 TLE See Temporal lobe epilepsy (TLE) Topiramate, 46–47, 232–233 Torsades de pointes (TdP), 45 Transient receptor potential (TRP), 26, 103–115 Transient receptor potential melastatin-4 (TRPM4) channel, 117–118 Transient receptor potential vanilloid type (TRPV1), 264–265, 277, 278f, 282–283 Transmembrane AMPA receptor regulatory proteins (TARPs) epilepsy, 235–236 stargazin, 216 Triazines (lamotrigine), 46 T-type Ca2+ channels (TTCCs), 115–116 Tumor necrosis factor-α (TNF-α), 177 TWIK-related K+ channel (TREK-1), 265, 277–279, 280f, 286–287 Two-pore domain potassium (K2P) channel, 265 glutamate, release pore for, 265 heteromeric channels, 265 KCNK1, KCNK2, KCNK10 mRNA expression, developmental regulation of, 281–282, 281f as pharmacological targets, 287–289 TASK1 and TASK3 mRNA, 279–281 TREK-1 channels, 265, 277–279, 280f, 286–287 TWIK-1, 286 V Valproate (VPT), 46–47, 178–179 Vaughan Williams classification, 44–45 Verapamil, 15–16, 59 VGCCs See Voltage-gated calcium channels (VGCCs) Vitamin C See Ascorbic acid Voltage-dependent anion channel-1 (VDAC1/porin-1), 118–120 Voltage-dependent facilitation (VDF), 55–56 Voltage-dependent inactivation (VDI), 38–39 Voltage-gated Ca2+ channels, channelopathies Cav1.1, 69–70 Cav1.2, 70–71 Cav1.3, 71 Cav1.4, 71 Cav2.1, 72–73 Cav ancillary subunit channelopathies, 76–77 Cav3 channels, 73 Voltage-gated calcium channels (VGCCs), 103–115, 118–120 386 Voltage-gated Na+ channels, channelopathies Nav1.1, 63–64 Nav1.2, 64–65 Nav1.4, 65 Nav1.5, 66–67 Nav1.6, 67 Nav1.7, 67–68 Nav1.8, 68 Nav1.9, 68–69 Nav β subunit channelopathies, 69 Subject Index Y γ-aminobutyric acid (GABA), 59–60, 98–99 Young Mania Rating Scale (YMRS), 178–179 Z Ziconitide, 59 Zinc, 183–185 Zonisamide, 121–125 ... excitatory or inhibitory effect For GABAARs, clathrin adaptor protein AP2 binds to the β and γ subunits, which in turn interact with clathrin, the GTPase dynamin, and other binding partners and form... function of the receptors, representing an emerging therapeutic strategy for corresponding channelopathies Advances in Protein Chemistry and Structural Biology, Volume 103 ISSN 1876-1623 http://dx.doi.org/10.1016/bs.apcsb.2015.11.002... Glycerine β loop interacts with E domain of gephyrin Gephyrin is also involved in the intracellular trafficking and lateral movement of glycine receptors (Fritschy, Harvey, & Schwarz, 2008) Gephyrin-induced