Pub Date : 2016-03-28DOI: 10.1080/19336950.2016.1164373
Daniela Gavello, E. Carbone, V. Carabelli
ABSTRACT Leptin is produced by adipose tissue and identified as a “satiety signal,” informing the brain when the body has consumed enough food. Specific areas of the hypothalamus express leptin receptors (LEPRs) and are the primary site of leptin action for body weight regulation. In response to leptin, appetite is suppressed and energy expenditure allowed. Beside this hypothalamic action, leptin targets other brain areas in addition to neuroendocrine cells. LEPRs are expressed also in the hippocampus, neocortex, cerebellum, substantia nigra, pancreatic β-cells, and chromaffin cells of the adrenal gland. It is intriguing how leptin is able to activate different ionic conductances, thus affecting excitability, synaptic plasticity and neurotransmitter release, depending on the target cell. Most of the intracellular pathways activated by leptin and directed to ion channels involve PI3K, which in turn phosphorylates different downstream substrates, although parallel pathways involve AMPK and MAPK. In this review we will describe the effects of leptin on BK, KATP, KV, CaV, TRPC, NMDAR and AMPAR channels and clarify the landscape of pathways involved. Given the ability of leptin to influence neuronal excitability and synaptic plasticity by modulating ion channels activity, we also provide a short overview of the growing potentiality of leptin as therapeutic agent for treating neurological disorders.
{"title":"Leptin-mediated ion channel regulation: PI3K pathways, physiological role, and therapeutic potential","authors":"Daniela Gavello, E. Carbone, V. Carabelli","doi":"10.1080/19336950.2016.1164373","DOIUrl":"https://doi.org/10.1080/19336950.2016.1164373","url":null,"abstract":"ABSTRACT Leptin is produced by adipose tissue and identified as a “satiety signal,” informing the brain when the body has consumed enough food. Specific areas of the hypothalamus express leptin receptors (LEPRs) and are the primary site of leptin action for body weight regulation. In response to leptin, appetite is suppressed and energy expenditure allowed. Beside this hypothalamic action, leptin targets other brain areas in addition to neuroendocrine cells. LEPRs are expressed also in the hippocampus, neocortex, cerebellum, substantia nigra, pancreatic β-cells, and chromaffin cells of the adrenal gland. It is intriguing how leptin is able to activate different ionic conductances, thus affecting excitability, synaptic plasticity and neurotransmitter release, depending on the target cell. Most of the intracellular pathways activated by leptin and directed to ion channels involve PI3K, which in turn phosphorylates different downstream substrates, although parallel pathways involve AMPK and MAPK. In this review we will describe the effects of leptin on BK, KATP, KV, CaV, TRPC, NMDAR and AMPAR channels and clarify the landscape of pathways involved. Given the ability of leptin to influence neuronal excitability and synaptic plasticity by modulating ion channels activity, we also provide a short overview of the growing potentiality of leptin as therapeutic agent for treating neurological disorders.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83628510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-10DOI: 10.1080/19336950.2016.1162365
Arijit Ghosh, Navneet Kaur, Abhishek Kumar, C. Goswami
ABSTRACT Every individual varies in character and so do their sensory functions and perceptions. The molecular mechanism and the molecular candidates involved in these processes are assumed to be similar if not same. So far several molecular factors have been identified which are fairly conserved across the phylogenetic tree and are involved in these complex sensory functions. Among all, members belonging to Transient Receptor Potential (TRP) channels have been widely characterized for their involvement in thermo-sensation. These include TRPV1 to TRPV4 channels which reveal complex thermo-gating behavior in response to changes in temperature. The molecular evolution of these channels is highly correlative with the thermal response of different species. However, recent 2504 human genome data suggest that these thermo-sensitive TRPV channels are highly variable and carry possible deleterious mutations in human population. These unexpected findings may explain the individual differences in terms of complex sensory functions.
{"title":"Why individual thermo sensation and pain perception varies? Clue of disruptive mutations in TRPVs from 2504 human genome data","authors":"Arijit Ghosh, Navneet Kaur, Abhishek Kumar, C. Goswami","doi":"10.1080/19336950.2016.1162365","DOIUrl":"https://doi.org/10.1080/19336950.2016.1162365","url":null,"abstract":"ABSTRACT Every individual varies in character and so do their sensory functions and perceptions. The molecular mechanism and the molecular candidates involved in these processes are assumed to be similar if not same. So far several molecular factors have been identified which are fairly conserved across the phylogenetic tree and are involved in these complex sensory functions. Among all, members belonging to Transient Receptor Potential (TRP) channels have been widely characterized for their involvement in thermo-sensation. These include TRPV1 to TRPV4 channels which reveal complex thermo-gating behavior in response to changes in temperature. The molecular evolution of these channels is highly correlative with the thermal response of different species. However, recent 2504 human genome data suggest that these thermo-sensitive TRPV channels are highly variable and carry possible deleterious mutations in human population. These unexpected findings may explain the individual differences in terms of complex sensory functions.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89455779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-10DOI: 10.1080/19336950.2016.1163956
J. Salvatierra, F. Bosmans
Within the voltage-gated NaC (Nav) channel gene family, the Nav1.7 isoform (SCN9A) has been receiving a great deal of scientific and clinical attention after investigators uncovered its strategic role in various pain syndromes. As a result, Nav1.7 became somewhat of a Holy Grail for researchers in academia as well as the pharmaceutical industry who are interested in discovering novel, target-specific non-narcotic pain therapeutics. However, clinically-used Nav channel drugs are prone to dose-limiting side effects because they typically target the conserved pore region and therefore do not discriminate between isoforms. In contrast, Nav channel voltage-sensing domains (VSDs) differ substantially between isoforms and regulate pore opening and closing (i.e. gating). As such, it should be possible to design effective drugs that target the gating process of a particular Nav channel isoform without physically blocking the pore, a fascinating concept that has recently led to the discovery of Nav1.7-specific small-molecule compounds. 4,5
{"title":"A painful tale about synthetic scorpion toxins","authors":"J. Salvatierra, F. Bosmans","doi":"10.1080/19336950.2016.1163956","DOIUrl":"https://doi.org/10.1080/19336950.2016.1163956","url":null,"abstract":"Within the voltage-gated NaC (Nav) channel gene family, the Nav1.7 isoform (SCN9A) has been receiving a great deal of scientific and clinical attention after investigators uncovered its strategic role in various pain syndromes. As a result, Nav1.7 became somewhat of a Holy Grail for researchers in academia as well as the pharmaceutical industry who are interested in discovering novel, target-specific non-narcotic pain therapeutics. However, clinically-used Nav channel drugs are prone to dose-limiting side effects because they typically target the conserved pore region and therefore do not discriminate between isoforms. In contrast, Nav channel voltage-sensing domains (VSDs) differ substantially between isoforms and regulate pore opening and closing (i.e. gating). As such, it should be possible to design effective drugs that target the gating process of a particular Nav channel isoform without physically blocking the pore, a fascinating concept that has recently led to the discovery of Nav1.7-specific small-molecule compounds. 4,5","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78783106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-03-07DOI: 10.1080/19336950.2016.1161988
R. W. Turner, Hadhimulya Asmara, J. Engbers, J. Miclat, Arsalan P. Rizwan, Giriraj Sahu, G. Zamponi
ABSTRACT Our previous work reported that KCa3.1 (IKCa) channels are expressed in CA1 hippocampal pyramidal cells and contribute to the slow afterhyperpolarization that regulates spike accommodation in these cells. The current report presents data from single cell RT-PCR that further reveals mRNA in CA1 cells that corresponds to the sequence of an IKCa channel from transmembrane segments 5 through 6 including the pore region, revealing the established binding sites for 4 different IKCa channel blockers. A comparison of methods to internally apply the IKCa channel blocker TRAM-34 shows that including the drug in an electrode from the onset of an experiment is unviable given the speed of drug action upon gaining access for whole-cell recordings. Together the data firmly establish IKCa channel expression in CA1 neurons and clarify methodological requirements to obtain a block of IKCa channel activity through internal application of TRAM-34.
{"title":"Assessing the role of IKCa channels in generating the sAHP of CA1 hippocampal pyramidal cells","authors":"R. W. Turner, Hadhimulya Asmara, J. Engbers, J. Miclat, Arsalan P. Rizwan, Giriraj Sahu, G. Zamponi","doi":"10.1080/19336950.2016.1161988","DOIUrl":"https://doi.org/10.1080/19336950.2016.1161988","url":null,"abstract":"ABSTRACT Our previous work reported that KCa3.1 (IKCa) channels are expressed in CA1 hippocampal pyramidal cells and contribute to the slow afterhyperpolarization that regulates spike accommodation in these cells. The current report presents data from single cell RT-PCR that further reveals mRNA in CA1 cells that corresponds to the sequence of an IKCa channel from transmembrane segments 5 through 6 including the pore region, revealing the established binding sites for 4 different IKCa channel blockers. A comparison of methods to internally apply the IKCa channel blocker TRAM-34 shows that including the drug in an electrode from the onset of an experiment is unviable given the speed of drug action upon gaining access for whole-cell recordings. Together the data firmly establish IKCa channel expression in CA1 neurons and clarify methodological requirements to obtain a block of IKCa channel activity through internal application of TRAM-34.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75153335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-22DOI: 10.1080/19336950.2016.1155900
L. Demirkhanyan, K. Uchida, M. Tominaga, E. Zakharian
Lusine Demirkhanyan, Kunitoshi Uchida, Makoto Tominaga, and Eleonora Zakharian Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA; Division of Cell Signaling, National Institute of Physiological Sciences (Okazaki Institute of Integrative Bioscience), Okazaki, Aichi, Japan; Department of Physiological Sciences, The Graduate University of Advanced Studies, Shonan Village, Hayama, Kanagawa, Japan
{"title":"TRPM3 gating in planar lipid bilayers defines peculiar agonist specificity","authors":"L. Demirkhanyan, K. Uchida, M. Tominaga, E. Zakharian","doi":"10.1080/19336950.2016.1155900","DOIUrl":"https://doi.org/10.1080/19336950.2016.1155900","url":null,"abstract":"Lusine Demirkhanyan, Kunitoshi Uchida, Makoto Tominaga, and Eleonora Zakharian Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL, USA; Division of Cell Signaling, National Institute of Physiological Sciences (Okazaki Institute of Integrative Bioscience), Okazaki, Aichi, Japan; Department of Physiological Sciences, The Graduate University of Advanced Studies, Shonan Village, Hayama, Kanagawa, Japan","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86999793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-18DOI: 10.1080/19336950.2016.1153210
M. Heine, A. Ciuraszkiewicz, A. Voigt, J. Heck, A. Bikbaev
ABSTRACT Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days. Even in the range of milliseconds, the composition and topology of ion channels are not static but engage in highly dynamic processes including stochastic or activity-dependent transient association of the pore-forming and auxiliary subunits, lateral diffusion, as well as clustering of different channels. In this review we briefly discuss the potential impact of mobile sodium, calcium and potassium ion channels and the functional significance of this for individual neurons and neuronal networks.
{"title":"Surface dynamics of voltage-gated ion channels","authors":"M. Heine, A. Ciuraszkiewicz, A. Voigt, J. Heck, A. Bikbaev","doi":"10.1080/19336950.2016.1153210","DOIUrl":"https://doi.org/10.1080/19336950.2016.1153210","url":null,"abstract":"ABSTRACT Neurons encode information in fast changes of the membrane potential, and thus electrical membrane properties are critically important for the integration and processing of synaptic inputs by a neuron. These electrical properties are largely determined by ion channels embedded in the membrane. The distribution of most ion channels in the membrane is not spatially uniform: they undergo activity-driven changes in the range of minutes to days. Even in the range of milliseconds, the composition and topology of ion channels are not static but engage in highly dynamic processes including stochastic or activity-dependent transient association of the pore-forming and auxiliary subunits, lateral diffusion, as well as clustering of different channels. In this review we briefly discuss the potential impact of mobile sodium, calcium and potassium ion channels and the functional significance of this for individual neurons and neuronal networks.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82862396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-18DOI: 10.1080/19336950.2016.1153203
Marie K. Bosch, J. Nerbonne, R. Reid Townsend, Haruko Miyazaki, N. Nukina, D. Ornitz, Céline Marionneau
ABSTRACT Intracellular Fibroblast Growth Factor 14 (iFGF14) and the other intracellular FGFs (iFGF11-13) regulate the properties and densities of voltage-gated neuronal and cardiac Na+ (Nav) channels. Recent studies have demonstrated that the iFGFs can also regulate native voltage-gated Ca2+ (Cav) channels. In the present study, a mass spectrometry (MS)-based proteomic approach was used to identify the components of native cerebellar iFGF14 complexes. Using an anti-iFGF14 antibody, native iFGF14 complexes were immunoprecipitated from wild type adult mouse cerebellum. Parallel control experiments were performed on cerebellar proteins isolated from mice (Fgf14−/−) harboring a targeted disruption of the Fgf14 locus. MS analyses of immunoprecipitated proteins demonstrated that the vast majority of proteins identified in native cerebellar iFGF14 complexes are Nav channel pore-forming (α) subunits or proteins previously reported to interact with Nav α subunits. In contrast, no Cav channel α or accessory subunits were revealed in cerebellar iFGF14 immunoprecipitates. Additional experiments were completed using an anti-PanNav antibody to immunoprecipitate Nav channel complexes from wild type and Fgf14−/− mouse cerebellum. Western blot and MS analyses revealed that the loss of iFGF14 does not measurably affect the protein composition or the relative abundance of Nav channel interacting proteins in native adult mouse cerebellar Nav channel complexes.
{"title":"Proteomic analysis of native cerebellar iFGF14 complexes","authors":"Marie K. Bosch, J. Nerbonne, R. Reid Townsend, Haruko Miyazaki, N. Nukina, D. Ornitz, Céline Marionneau","doi":"10.1080/19336950.2016.1153203","DOIUrl":"https://doi.org/10.1080/19336950.2016.1153203","url":null,"abstract":"ABSTRACT Intracellular Fibroblast Growth Factor 14 (iFGF14) and the other intracellular FGFs (iFGF11-13) regulate the properties and densities of voltage-gated neuronal and cardiac Na+ (Nav) channels. Recent studies have demonstrated that the iFGFs can also regulate native voltage-gated Ca2+ (Cav) channels. In the present study, a mass spectrometry (MS)-based proteomic approach was used to identify the components of native cerebellar iFGF14 complexes. Using an anti-iFGF14 antibody, native iFGF14 complexes were immunoprecipitated from wild type adult mouse cerebellum. Parallel control experiments were performed on cerebellar proteins isolated from mice (Fgf14−/−) harboring a targeted disruption of the Fgf14 locus. MS analyses of immunoprecipitated proteins demonstrated that the vast majority of proteins identified in native cerebellar iFGF14 complexes are Nav channel pore-forming (α) subunits or proteins previously reported to interact with Nav α subunits. In contrast, no Cav channel α or accessory subunits were revealed in cerebellar iFGF14 immunoprecipitates. Additional experiments were completed using an anti-PanNav antibody to immunoprecipitate Nav channel complexes from wild type and Fgf14−/− mouse cerebellum. Western blot and MS analyses revealed that the loss of iFGF14 does not measurably affect the protein composition or the relative abundance of Nav channel interacting proteins in native adult mouse cerebellar Nav channel complexes.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83068039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-08DOI: 10.1080/19336950.2015.1134068
Y. Jeong, J. Hong
ABSTRACT Anion exchanger 2 (AE2) has a critical role in epithelial cells and is involved in the ionic homeostasis such as Cl− uptake and HCO3− secretion. However, little is known about the regulatory mechanism of AE2. The main goal of the present study was to investigate potential regulators, such as spinophilin (SPL), inositol-1,4,5-trisphosphate [IP3] receptors binding protein released with IP3 (IRBIT), STE20/SPS1-related proline/alanine-rich kinase (SPAK) kinase, and carbonic anhydrase XII (CA XII). We found that SPL binds to AE2 and markedly increased the Cl−/HCO3− exchange activity of AE2. Especially SPL 1–480 domain is required for enhancing AE2 activity. For other regulatory components that affect the fidelity of fluid and HCO3− secretion, IRBIT and SPAK had no effect on the activity of AE2 and no protein-protein interaction with AE2. It has been proposed that CA activity is closely associated with AE activity. In this study, we provide evidence that the basolateral membrane-associated CA isoform CA XII significantly increased the activity of AE2 and co-localized with AE2 to the plasma membrane. Collectively, SPL and CA XII enhanced the Cl−/HCO3− exchange activity of AE2. The modulating action of these regulatory proteins could serve as potential therapeutic targets for secretory diseases mediated by AE2.
{"title":"Governing effect of regulatory proteins for Cl−/HCO3− exchanger 2 activity","authors":"Y. Jeong, J. Hong","doi":"10.1080/19336950.2015.1134068","DOIUrl":"https://doi.org/10.1080/19336950.2015.1134068","url":null,"abstract":"ABSTRACT Anion exchanger 2 (AE2) has a critical role in epithelial cells and is involved in the ionic homeostasis such as Cl− uptake and HCO3− secretion. However, little is known about the regulatory mechanism of AE2. The main goal of the present study was to investigate potential regulators, such as spinophilin (SPL), inositol-1,4,5-trisphosphate [IP3] receptors binding protein released with IP3 (IRBIT), STE20/SPS1-related proline/alanine-rich kinase (SPAK) kinase, and carbonic anhydrase XII (CA XII). We found that SPL binds to AE2 and markedly increased the Cl−/HCO3− exchange activity of AE2. Especially SPL 1–480 domain is required for enhancing AE2 activity. For other regulatory components that affect the fidelity of fluid and HCO3− secretion, IRBIT and SPAK had no effect on the activity of AE2 and no protein-protein interaction with AE2. It has been proposed that CA activity is closely associated with AE activity. In this study, we provide evidence that the basolateral membrane-associated CA isoform CA XII significantly increased the activity of AE2 and co-localized with AE2 to the plasma membrane. Collectively, SPL and CA XII enhanced the Cl−/HCO3− exchange activity of AE2. The modulating action of these regulatory proteins could serve as potential therapeutic targets for secretory diseases mediated by AE2.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79446993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-02-06DOI: 10.1080/19336950.2016.1148224
Natalie E. Smith, B. Corry
ABSTRACT Voltage gated sodium channels are the target of a range of local anesthetic, anti-epileptic and anti-arrhythmic compounds. But, gaining a molecular level understanding of their mode of action is difficult as we only have atomic resolution structures of bacterial sodium channels not their eukaryotic counterparts. In this study we used molecular dynamics simulations to demonstrate that the binding sites of both the local anesthetic benzocaine and the anti-epileptic phenytoin to the bacterial sodium channel NavAb can be altered significantly by the introduction of point mutations. Free energy techniques were applied to show that increased aromaticity in the pore of the channel, used to emulate the aromatic residues observed in eukaryotic Nav1.2, led to changes in the location of binding and dissociation constants of each drug relative to wild type NavAb. Further, binding locations and dissociation constants obtained for both benzocaine (660 μM) and phenytoin (1 μ M) in the mutant channels were within the range expected from experimental values obtained from drug binding to eukaryotic sodium channels, indicating that these mutant NavAb may be a better model for drug binding to eukaryotic channels than the wild type.
{"title":"Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins","authors":"Natalie E. Smith, B. Corry","doi":"10.1080/19336950.2016.1148224","DOIUrl":"https://doi.org/10.1080/19336950.2016.1148224","url":null,"abstract":"ABSTRACT Voltage gated sodium channels are the target of a range of local anesthetic, anti-epileptic and anti-arrhythmic compounds. But, gaining a molecular level understanding of their mode of action is difficult as we only have atomic resolution structures of bacterial sodium channels not their eukaryotic counterparts. In this study we used molecular dynamics simulations to demonstrate that the binding sites of both the local anesthetic benzocaine and the anti-epileptic phenytoin to the bacterial sodium channel NavAb can be altered significantly by the introduction of point mutations. Free energy techniques were applied to show that increased aromaticity in the pore of the channel, used to emulate the aromatic residues observed in eukaryotic Nav1.2, led to changes in the location of binding and dissociation constants of each drug relative to wild type NavAb. Further, binding locations and dissociation constants obtained for both benzocaine (660 μM) and phenytoin (1 μ M) in the mutant channels were within the range expected from experimental values obtained from drug binding to eukaryotic sodium channels, indicating that these mutant NavAb may be a better model for drug binding to eukaryotic channels than the wild type.","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83248049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2016-01-26DOI: 10.1080/19336950.2015.1119633
M. Dittrich, S. D. Meriney
A key property of many synapses in the nervous system is their ability to trigger fast fusion of transmitter-containing vesicles at specialized release sites (active zones; AZs). This raises the qu...
神经系统中许多突触的一个关键特性是它们能够在特定的释放位点(活跃区;az)。这就提出了…
{"title":"Single calcium channels stand out in the crowd","authors":"M. Dittrich, S. D. Meriney","doi":"10.1080/19336950.2015.1119633","DOIUrl":"https://doi.org/10.1080/19336950.2015.1119633","url":null,"abstract":"A key property of many synapses in the nervous system is their ability to trigger fast fusion of transmitter-containing vesicles at specialized release sites (active zones; AZs). This raises the qu...","PeriodicalId":9750,"journal":{"name":"Channels","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2016-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82926871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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