Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.78256
Tianbo Li, Jun Chen
Voltage-gated sodium channels (Nav) control the initiation and propagation of action potential, and thus mediate a broad spectrum of physiological processes, including central and peripheral nervous systems ’ function, skeletal muscle contraction, and heart rhythm. Recent advances in elucidating the molecular basis of channelopathies implicating Nav channels are the most appealing druggable targets for pain and many other pathology conditions. This chapter overviews Nav super family from genetic evolution, distribution, human diseases/pathology association, highlighting the most recent structure function breakthrough. The second section will discuss current small and large Nav modulators, including traditional nonselective pore blockers, intracellular modulators, and extracellular modulators.
{"title":"Voltage-Gated Sodium Channels in Drug Discovery","authors":"Tianbo Li, Jun Chen","doi":"10.5772/INTECHOPEN.78256","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.78256","url":null,"abstract":"Voltage-gated sodium channels (Nav) control the initiation and propagation of action potential, and thus mediate a broad spectrum of physiological processes, including central and peripheral nervous systems ’ function, skeletal muscle contraction, and heart rhythm. Recent advances in elucidating the molecular basis of channelopathies implicating Nav channels are the most appealing druggable targets for pain and many other pathology conditions. This chapter overviews Nav super family from genetic evolution, distribution, human diseases/pathology association, highlighting the most recent structure function breakthrough. The second section will discuss current small and large Nav modulators, including traditional nonselective pore blockers, intracellular modulators, and extracellular modulators.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"25 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123652018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.76390
Tian Li
In the past decade, hundreds of mutations have been found in the SCN1A (sodium voltage-gated channel α subunit 1) gene in the epileptic patients. The functioning of the SCN1A gene products is intensively studied in the neuroscience field. The loss-of-function mutations of the SCN1A gene are the causative factor of Dravet syndrome, an intractable epilepsy syndrome. With the loss-of-function Na v 1.1 (the protein encoded by SCN1A gene), the selective dysfunction of the inhibitory parvalbumin (PV) interneurons impairs the balance of excitatory and inhibitory synaptic inputs to the downstream neurons, and causes the hyperexcitability of the neuronal network. The underlying mechanism is that the axon initial segments (AISs) of inhibitory parvalbumin interneurons predominantly express Na v 1.1, particularly in the proximal end of the AISs. The deficiency of Na v 1.1 weakens the excitability of the inhibitory parvalbumin neurons and leads to the hyperexcitability of the neuronal network. The sodium channel blockers, one category of the antiepileptic drugs (AEDs) that specifically block the activity of VGSCs, may potentially worsen the defect of Na v 1.1 of the PV interneurons in the patients with the SCN1A gene loss-of-function mutations, the clinical manifestation, and increase the seizure frequency of those patients.
在过去的十年中，在癫痫患者的SCN1A(钠电压门控通道α亚基1)基因中发现了数百个突变。SCN1A基因产物的功能在神经科学领域得到了广泛的研究。SCN1A基因的功能缺失突变是一种顽固性癫痫综合征——Dravet综合征的致病因素。随着Na v1.1 (SCN1A基因编码的蛋白)的功能缺失，抑制性小白蛋白(PV)中间神经元的选择性功能障碍损害了下游神经元兴奋性和抑制性突触输入的平衡，并导致神经元网络的高兴奋性。其潜在机制是抑制小白蛋白中间神经元的轴突初始段(AISs)主要表达Na v 1.1，特别是在AISs的近端。Na v1.1缺乏使抑制性小蛋白神经元的兴奋性减弱，导致神经元网络的高兴奋性。钠通道阻滞剂是一类特异性阻断VGSCs活性的抗癫痫药物(AEDs)，可能会使SCN1A基因功能缺失突变患者PV中间神经元Na v 1.1缺陷加重临床表现，增加患者癫痫发作频率。
{"title":"Genetic Defects of Voltage-Gated Sodium Channel α Subunit 1 in Dravet Syndrome and the Patients’ Response to Antiepileptic Drugs","authors":"Tian Li","doi":"10.5772/INTECHOPEN.76390","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.76390","url":null,"abstract":"In the past decade, hundreds of mutations have been found in the SCN1A (sodium voltage-gated channel α subunit 1) gene in the epileptic patients. The functioning of the SCN1A gene products is intensively studied in the neuroscience field. The loss-of-function mutations of the SCN1A gene are the causative factor of Dravet syndrome, an intractable epilepsy syndrome. With the loss-of-function Na v 1.1 (the protein encoded by SCN1A gene), the selective dysfunction of the inhibitory parvalbumin (PV) interneurons impairs the balance of excitatory and inhibitory synaptic inputs to the downstream neurons, and causes the hyperexcitability of the neuronal network. The underlying mechanism is that the axon initial segments (AISs) of inhibitory parvalbumin interneurons predominantly express Na v 1.1, particularly in the proximal end of the AISs. The deficiency of Na v 1.1 weakens the excitability of the inhibitory parvalbumin neurons and leads to the hyperexcitability of the neuronal network. The sodium channel blockers, one category of the antiepileptic drugs (AEDs) that specifically block the activity of VGSCs, may potentially worsen the defect of Na v 1.1 of the PV interneurons in the patients with the SCN1A gene loss-of-function mutations, the clinical manifestation, and increase the seizure frequency of those patients.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129649553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.76479
W. Cheng
Transient receptor potential (TRP) ion channel superfamily is widely distributed from neuronal to non-neuronal tissues by serving as cellular sensors via interacting with a wide spectrum of physical and chemical stimuli. TRP ion channels are tetrameric protein complexes. Accordingly, TRP subunits can form functional both homomeric channels and heteromeric channels which either in the same subfamily or in the different subfamilies to diversify TRP channel functions. In this chapter, we will briefly introduce this fascinating ion channel superfamily. Further, we will summarize current knowledge on mammalian TRP ion channels distribution in tissues and organs as well as assembly of these ion channel subunits. Implications and related physiological roles regarding distribution and assembly will be overviewed as well.
{"title":"TRP Ion Channels: From Distribution to Assembly","authors":"W. Cheng","doi":"10.5772/INTECHOPEN.76479","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.76479","url":null,"abstract":"Transient receptor potential (TRP) ion channel superfamily is widely distributed from neuronal to non-neuronal tissues by serving as cellular sensors via interacting with a wide spectrum of physical and chemical stimuli. TRP ion channels are tetrameric protein complexes. Accordingly, TRP subunits can form functional both homomeric channels and heteromeric channels which either in the same subfamily or in the different subfamilies to diversify TRP channel functions. In this chapter, we will briefly introduce this fascinating ion channel superfamily. Further, we will summarize current knowledge on mammalian TRP ion channels distribution in tissues and organs as well as assembly of these ion channel subunits. Implications and related physiological roles regarding distribution and assembly will be overviewed as well.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"1203 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121457418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.77996
C. Castro-Junior, L. Ferreira, M. Delgado, J. F. Silva, D. C. Santos
Calcium-permeable channels control intracellular calcium dynamics in both neuronal and nonneuronal cells to orchestrate sensory functions including pain. Calcium entering the cell throughout these channels is associated with transduction, transmission, processing, and modulation of pain signals. Clinic, genetic, biochemical, biophysical and pharmacological evidence points toward calcium-permeable channels as the key players in acute and persistent pain conditions. Ligand-gated calcium channels such as TRP channels or some subtypes of voltage-gated calcium channels shows abnormal functioning in persis- tent pain states. Also, NMDA receptors can be unlocked from their physiological Mg 2+ blockade under persisten pain states to culminate with central sensitization. The primary goal of this chapter is to present an overview of the functioning of different classes of calcium-permeable channels and how they become altered to modulate the sensation of pain in acute and chronic states. The most important evidence from classical and recent studies will be discussed trying to depict ways of modulating those channels as a strategy for better pain control.
{"title":"Role of Calcium Permeable Channels in Pain Processing","authors":"C. Castro-Junior, L. Ferreira, M. Delgado, J. F. Silva, D. C. Santos","doi":"10.5772/INTECHOPEN.77996","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.77996","url":null,"abstract":"Calcium-permeable channels control intracellular calcium dynamics in both neuronal and nonneuronal cells to orchestrate sensory functions including pain. Calcium entering the cell throughout these channels is associated with transduction, transmission, processing, and modulation of pain signals. Clinic, genetic, biochemical, biophysical and pharmacological evidence points toward calcium-permeable channels as the key players in acute and persistent pain conditions. Ligand-gated calcium channels such as TRP channels or some subtypes of voltage-gated calcium channels shows abnormal functioning in persis- tent pain states. Also, NMDA receptors can be unlocked from their physiological Mg 2+ blockade under persisten pain states to culminate with central sensitization. The primary goal of this chapter is to present an overview of the functioning of different classes of calcium-permeable channels and how they become altered to modulate the sensation of pain in acute and chronic states. The most important evidence from classical and recent studies will be discussed trying to depict ways of modulating those channels as a strategy for better pain control.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"61 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130930810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.77732
V. Szűts, J. Jarabin, N. Nagy, F. Otvos, R. Nagy, Attila L Nagy, K. Halasy, L. Rovó, M. Széll, J. Kiss
Connexins, Kv-type ion channels, and pannexins have a dominant role in maintaining the potassium ion homeostasis in the cochlea. The cellular background currents are sustained by Kir2.1 ion channels; however, their involvement in the hearing system is less clear. In this study, the mutations of gap junction proteins beta 2 (GJB2), beta 3 (GJB3) and beta 6 (GJB6) were screened in the white Caucasian population in Hungary using gene mapping and immunofluorescence methods from translated proteins of these genes—connexins on blood cells. Expression of connexins and Kir2.1 ion channels was investigated in the blood cells of deaf patients prior to cochlear implantation, and the results show significantly decreased amounts of connexin26 and connexin43. In addition, the coexpression of Kir2.1 ion channels with synapse-associated 97 proteins was partially impaired. Our investigation revealed a reduced level of Kir2.1 channels in deaf patients indicating a crucial role for the functional Shaker superfamily of K+ channels in the non-diseased hearing system.
{"title":"Altered Potassium Ion Homeostasis in Hearing Loss","authors":"V. Szűts, J. Jarabin, N. Nagy, F. Otvos, R. Nagy, Attila L Nagy, K. Halasy, L. Rovó, M. Széll, J. Kiss","doi":"10.5772/INTECHOPEN.77732","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.77732","url":null,"abstract":"Connexins, Kv-type ion channels, and pannexins have a dominant role in maintaining the potassium ion homeostasis in the cochlea. The cellular background currents are sustained by Kir2.1 ion channels; however, their involvement in the hearing system is less clear. In this study, the mutations of gap junction proteins beta 2 (GJB2), beta 3 (GJB3) and beta 6 (GJB6) were screened in the white Caucasian population in Hungary using gene mapping and immunofluorescence methods from translated proteins of these genes—connexins on blood cells. Expression of connexins and Kir2.1 ion channels was investigated in the blood cells of deaf patients prior to cochlear implantation, and the results show significantly decreased amounts of connexin26 and connexin43. In addition, the coexpression of Kir2.1 ion channels with synapse-associated 97 proteins was partially impaired. Our investigation revealed a reduced level of Kir2.1 channels in deaf patients indicating a crucial role for the functional Shaker superfamily of K+ channels in the non-diseased hearing system.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"26 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121269766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.76419
Katarina Mackova, A. Mišák, Z. Tomášková
The current through mitochondrial chloride channels was first described in 1987. Subsequently, several types of ion channels permeable to chloride and other anions were found in the mitochondria of different origins. The increasing number of electrophysi - ological studies, however, yielded only more ambiguity rather than order in the field of chloride channels. This uncertainty was slightly reduced by two different studies: experi - ments that showed a significant role of chloride channels in the process of mitochondrial membrane potential oscillations and experiments that localized chloride intracellular ion channel (CLIC) proteins in cardiac mitochondrial membranes. Our recently published single-channel electrophysiological experiments are well in line with the channel activity of recombinant CLIC proteins. The experimental evidence seems to be inevitably, though slowly converging on a connection between single-channel activity and the identity of the mitochondrial chloride channel protein.
{"title":"Lifting the Fog over Mitochondrial Chloride Channels","authors":"Katarina Mackova, A. Mišák, Z. Tomášková","doi":"10.5772/INTECHOPEN.76419","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.76419","url":null,"abstract":"The current through mitochondrial chloride channels was first described in 1987. Subsequently, several types of ion channels permeable to chloride and other anions were found in the mitochondria of different origins. The increasing number of electrophysi - ological studies, however, yielded only more ambiguity rather than order in the field of chloride channels. This uncertainty was slightly reduced by two different studies: experi - ments that showed a significant role of chloride channels in the process of mitochondrial membrane potential oscillations and experiments that localized chloride intracellular ion channel (CLIC) proteins in cardiac mitochondrial membranes. Our recently published single-channel electrophysiological experiments are well in line with the channel activity of recombinant CLIC proteins. The experimental evidence seems to be inevitably, though slowly converging on a connection between single-channel activity and the identity of the mitochondrial chloride channel protein.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129623503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.80597
K. F. Shad, Saad Salman, S. Afridi, Muniba Tariq, Sajid Asghar
{"title":"Introductory Chapter: Ion Channels","authors":"K. F. Shad, Saad Salman, S. Afridi, Muniba Tariq, Sajid Asghar","doi":"10.5772/INTECHOPEN.80597","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.80597","url":null,"abstract":"","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"56 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116521239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.80370
Tianbo Li, Jun Chen
Voltage-gated sodium (Nav) channels represent an important class of drug target for pain and many other pathology conditions. Despite the recent advances in channelopa-thies and structure-function studies, the discovery of Nav channel therapeutics is still facing a major challenge from the limitation of assay technologies. This chapter will focus on advancement and challenge of Nav drug discovery technologies including nonelec- trophysiological assays, extracellular electrophysiological assays, and the newly evolved high-throughput automated patch clamp (APC) technologies.
{"title":"Voltage-Gated Sodium Channel Drug Discovery Technologies and Challenges","authors":"Tianbo Li, Jun Chen","doi":"10.5772/INTECHOPEN.80370","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.80370","url":null,"abstract":"Voltage-gated sodium (Nav) channels represent an important class of drug target for pain and many other pathology conditions. Despite the recent advances in channelopa-thies and structure-function studies, the discovery of Nav channel therapeutics is still facing a major challenge from the limitation of assay technologies. This chapter will focus on advancement and challenge of Nav drug discovery technologies including nonelec- trophysiological assays, extracellular electrophysiological assays, and the newly evolved high-throughput automated patch clamp (APC) technologies.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"91 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114420322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-10-10DOI: 10.5772/INTECHOPEN.77305
Tianhua Feng, S. Kalyaanamoorthy, K. Barakat
Voltage-gated calcium channels (VGCCs) manage the electrical signaling of cells by allowing the selective-diffusion of calcium ions in response to the changes in the cellular membrane potential. Among the different VGCCs, the long-lasting or the L-type calcium channels (LTCCs) are prevalently expressed in a variety of cells, such as skeletal muscle, ventricular myocytes, smooth muscles and dendritic cells and forms the largest family of the VGCCs. Their wide expression pattern and significant role in diverse cellular events, including neurotransmission, cell cycle, muscular contraction, cardiac action potential and gene expression, has made these channels the major targets for drug development. In this book chapter, we aim to provide a comprehensive overview of the different VGCCs and focus on the sequence-structure–function properties of the LTCCs. Our chapter will summarize and review the various experimental and computational analyses performed on the structures of the LTCCs and their implications in drug discovery applications.
{"title":"L-Type Calcium Channels: Structure and Functions","authors":"Tianhua Feng, S. Kalyaanamoorthy, K. Barakat","doi":"10.5772/INTECHOPEN.77305","DOIUrl":"https://doi.org/10.5772/INTECHOPEN.77305","url":null,"abstract":"Voltage-gated calcium channels (VGCCs) manage the electrical signaling of cells by allowing the selective-diffusion of calcium ions in response to the changes in the cellular membrane potential. Among the different VGCCs, the long-lasting or the L-type calcium channels (LTCCs) are prevalently expressed in a variety of cells, such as skeletal muscle, ventricular myocytes, smooth muscles and dendritic cells and forms the largest family of the VGCCs. Their wide expression pattern and significant role in diverse cellular events, including neurotransmission, cell cycle, muscular contraction, cardiac action potential and gene expression, has made these channels the major targets for drug development. In this book chapter, we aim to provide a comprehensive overview of the different VGCCs and focus on the sequence-structure–function properties of the LTCCs. Our chapter will summarize and review the various experimental and computational analyses performed on the structures of the LTCCs and their implications in drug discovery applications.","PeriodicalId":205619,"journal":{"name":"Ion Channels in Health and Sickness","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115013966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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