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https://www.readbyqxmd.com/read/29163198/ankyrins-and-spectrins-in-cardiovascular-biology-and-disease
#1
REVIEW
Mona M El Refaey, Peter J Mohler
Ankyrins are adaptor proteins critical for the expression and targeting of cardiac membrane proteins, signaling molecules, and cytoskeletal elements. Findings in humans and animal models have highlighted the in vivo roles for ankyrins in normal physiology and in cardiovascular disease, most notably in cardiac arrhythmia. For example, human ANK2 loss-of-function variants are associated with a complex array of electrical and structural phenotypes now termed "ankyrin-B syndrome," whereas alterations in the ankyrin-G pathway for Nav channel targeting are associated with human Brugada syndrome...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29161016/selective-voltage-gated-sodium-channel-peptide-toxins-from-animal-venom-pharmacological-probes-and-analgesic-drug-development
#2
Ying Wu, Hui Ma, Fan Zhang, Chun-Lei Zhang, Xiaohan Zou, Zhengyu Cao
Voltage-gated sodium channels (Navs) play critical roles in action potential generation and propagation. Nav channelopathy as well as pathological sensitization contribute to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8 and 1.9) in nociceptive transduction and therefore these Navs may represent attractive targets for analgesic drug discovery. Animal toxins are structurally diverse peptides that are highly potent yet selective on ion channel subtypes and therefore representing valuable probes to elucidate the structures, gating properties and cellular functions of ion channels...
November 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29142310/sodium-channel-nav1-3-is-important-for-enterochromaffin-cell-excitability-and-serotonin-release
#3
Peter R Strege, Kaitlyn Knutson, Samuel J Eggers, Joyce H Li, Fan Wang, David Linden, Joseph H Szurszewski, Lorin Milescu, Andrew B Leiter, Gianrico Farrugia, Arthur Beyder
In the gastrointestinal (GI) epithelium, enterochromaffin (EC) cells are enteroendocrine cells responsible for producing >90% of the body's serotonin (5-hydroxytryptamine, 5-HT). However, the molecular mechanisms of EC cell function are poorly understood. Here, we found that EC cells in mouse primary cultures fired spontaneous bursts of action potentials. We examined the repertoire of voltage-gated sodium channels (NaV) in fluorescence-sorted mouse EC cells and found that Scn3a was highly expressed. Scn3a-encoded NaV1...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29138838/effects-of-scn9a-gene-modification-on-na-channel-and-the-expression-of-nerve-growth-factor-in-a-rat-model-of-diarrhea%C3%A2-predominant-irritable-bowel-syndrome
#4
Yong-Yan Cai, Chen Li, Zhi-Xin Yan, Na Ma, Fang-Fang Li
The aim of the present study was to identify whether the sodium voltage-gated channel alpha subunit 9 (SCN9A) gene modification is a potential treatment for diarrhea‑predominant irritable bowel syndrome (D‑IBS), via regulating the Na+ channel and the expression of nerve growth factor (NGF). The recombinant adenovirus vector of the SCN9A gene was established, and rat colon cells were isolated for SCN9A gene modification. All subjects were divided into four groups: i) The SCN9A‑modified (D‑IBS rat model implanted with SCN9A‑modified colon cells), ii) negative control (NC; D‑IBS rat model implanted with colon cells without SCN9A gene modification), iii) blank (D‑IBS rat model without any treatment) and iv) normal (normal rats without any treatment)...
November 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29109270/m-current-inhibition-rapidly-induces-a-unique-ck2-dependent-plasticity-of-the-axon-initial-segment
#5
Jonathan Lezmy, Maya Lipinsky, Yana Khrapunsky, Eti Patrich, Lia Shalom, Asher Peretz, Ilya A Fleidervish, Bernard Attali
Alterations in synaptic input, persisting for hours to days, elicit homeostatic plastic changes in the axon initial segment (AIS), which is pivotal for spike generation. Here, in hippocampal pyramidal neurons of both primary cultures and slices, we triggered a unique form of AIS plasticity by selectively targeting M-type K(+) channels, which predominantly localize to the AIS and are essential for tuning neuronal excitability. While acute M-current inhibition via cholinergic activation or direct channel block made neurons more excitable, minutes to hours of sustained M-current depression resulted in a gradual reduction in intrinsic excitability...
November 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29101377/a-high-throughput-model-for-investigating-neuronal-function-and-synaptic-transmission-in-cultured-neuronal-networks
#6
Jasmeet K Virdee, Gabriella Saro, Antoine Fouillet, Jeremy Findlay, Filipa Ferreira, Sarah Eversden, Michael J O'Neill, Joanna Wolak, Daniel Ursu
Loss of synapses or alteration of synaptic activity is associated with cognitive impairment observed in a number of psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. Therefore successful development of in vitro methods that can investigate synaptic function in a high-throughput format could be highly impactful for neuroscience drug discovery. We present here the development, characterisation and validation of a novel high-throughput in vitro model for assessing neuronal function and synaptic transmission in primary rodent neurons...
November 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29094210/evolutionary-history-of-voltage-gated-sodium-channels
#7
Atsuo Nishino, Yasushi Okamura
Every cell within living organisms actively maintains an intracellular Na(+) concentration that is 10-12 times lower than the extracellular concentration. The cells then utilize this transmembrane Na(+) concentration gradient as a driving force to produce electrical signals, sometimes in the form of action potentials. The protein family comprising voltage-gated sodium channels (NaVs) is essential for such signaling and enables cells to change their status in a regenerative manner and to rapidly communicate with one another...
November 2, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29079725/complementary-mechanisms-for-neurotoxin-resistance-in-a-copepod
#8
Vittoria Roncalli, Petra H Lenz, Matthew C Cieslak, Daniel K Hartline
Toxin resistance is a recurring evolutionary response by predators feeding on toxic prey. These adaptations impact physiological interaction and community ecology. Mechanisms for resistance vary depending on the predator and the nature of the toxin. Potent neurotoxins like tetrodotoxin (TTX) and saxitoxin (STX) that are highly toxic to humans and other vertebrates, target conserved voltage-gated sodium channels (NaV) of nerve and muscle, causing paralysis. The copepod Calanus finmarchicus consumes the STX-producing dinoflagellate, Alexandrium fundyense with no effect on survival...
October 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29077258/whole-exome-sequencing-identifies-a-novel-mutation-of-gpd1l-r189x-associated-with-familial-conduction-disease-and-sudden-death
#9
Hao Huang, Ya-Qin Chen, Liang-Liang Fan, Shuai Guo, Jing-Jing Li, Jie-Yuan Jin, Rong Xiang
Cardiac conduction disease (CCD) is a serious disorder and the leading cause of mortality worldwide. It is characterized by arrhythmia, syncope or even sudden cardiac death caused by the dysfunction of cardiac voltage-gated channel. Previous study has demonstrated that mutations in genes encoding voltage-gated channel and related proteins were the crucial genetic lesion of CCD. In this study, we employed whole-exome sequencing to explore the potential causative genes in a Chinese family with ventricular tachycardia and syncope...
October 27, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29055053/expression-patterns-of-ion-channels-and-structural-proteins-in-a-multimodal-cell-type-of-the-avian-optic-tectum
#10
Katharina Lischka, Simone Ladel, Harald Luksch, Stefan Weigel
The midbrain is an important subcortical area involved in distinct functions such as multimodal integration, movement initiation, bottom-up and top-down attention. Our group is particularly interested in cellular computation of multisensory integration. We focus on the visual part of the avian midbrain, the optic tectum (TeO, counterpart to mammalian superior colliculus). This area has a layered structure with the great advantage of distinct in- and output regions. In chicken, the TeO is organized in 15 layers where visual input targets the superficial layers while auditory input terminates in deeper layers...
October 21, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/29032483/regulation-of-cardiac-voltage-gated-sodium-channel-by-kinases-roles-of-protein-kinases-a-and-c
#11
Ademuyiwa S Aromolaran, Mohamed Chahine, Mohamed Boutjdir
In the heart, voltage-gated sodium (Nav) channel (Nav1.5) is defined by its pore-forming α-subunit and its auxiliary β-subunits, both of which are important for its critical contribution to the initiation and maintenance of the cardiac action potential (AP) that underlie normal heart rhythm. The physiological relevance of Nav1.5 is further marked by the fact that inherited or congenital mutations in Nav1.5 channel gene SCN5A lead to altered functional expression (including expression, trafficking, and current density), and are generally manifested in the form of distinct cardiac arrhythmic events, epilepsy, neuropathic pain, migraine, and neuromuscular disorders...
October 15, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29030712/calculating-the-consequences-of-left-shifted-nav-channel-activity-in-sick-excitable-cells
#12
Bela Joos, Benjamin M Barlow, Catherine E Morris
Two features common to diverse sick excitable cells are "leaky" Nav channels and bleb damage-damaged membranes. The bleb damage, we have argued, causes a channel kinetics based "leakiness." Recombinant (node of Ranvier type) Nav1.6 channels voltage-clamped in mechanically-blebbed cell-attached patches undergo a damage intensity dependent kinetic change. Specifically, they experience a coupled hyperpolarizing (left) shift of the activation and inactivation processes. The biophysical observations on Nav1.6 currents formed the basis of Nav-Coupled Left Shift (Nav-CLS) theory...
October 14, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29027912/guanidinium-toxins-and-their-interactions-with-voltage-gated-sodium-ion-channels
#13
REVIEW
Lorena M Durán-Riveroll, Allan D Cembella
Guanidinium toxins, such as saxitoxin (STX), tetrodotoxin (TTX) and their analogs, are naturally occurring alkaloids with divergent evolutionary origins and biogeographical distribution, but which share the common chemical feature of guanidinium moieties. These guanidinium groups confer high biological activity with high affinity and ion flux blockage capacity for voltage-gated sodium channels (NaV). Members of the STX group, known collectively as paralytic shellfish toxins (PSTs), are produced among three genera of marine dinoflagellates and about a dozen genera of primarily freshwater or brackish water cyanobacteria...
October 13, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28939972/effects-of-benzothiazolamines-on-voltage-gated-sodium-channels
#14
Alessandro Farinato, Concetta Altamura, Jean-François Desaphy
Benzothiazole is a versatile fused heterocycle that aroused much interest in drug discovery as anticonvulsant, neuroprotective, analgesic, anti-inflammatory, antimicrobial, and anticancer. Two benzothiazolamines, riluzole and lubeluzole, are known blockers of voltage-gated sodium (Nav) channels. Riluzole is clinically used as a neuroprotectant in amyotrophic lateral sclerosis. Inhibition of Nav channels by riluzole is voltage-dependent due to preferential binding to inactivated sodium channels. Yet the drug exerts little use-dependent block, probably because it lacks protonable amine...
September 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28931746/voltage-gated-sodium-channel-gene-repertoire-of-lampreys-gene-duplications-tissue-specific-expression-and-discovery-of-a-long-lost-gene
#15
Harold H Zakon, Weiming Li, Nisha E Pillai, Sumanty Tohari, Prashant Shingate, Jianfeng Ren, Byrappa Venkatesh
Studies of the voltage-gated sodium (Nav) channels of extant gnathostomes have made it possible to deduce that ancestral gnathostomes possessed four voltage-gated sodium channel genes derived from a single ancestral chordate gene following two rounds of genome duplication early in vertebrates. We investigated the Nav gene family in two species of lampreys (the Japanese lamprey Lethenteron japonicum and sea lamprey Petromyzon marinus) (jawless vertebrates-agnatha) and compared them with those of basal vertebrates to better understand the origin of Nav genes in vertebrates...
September 27, 2017: Proceedings. Biological Sciences
https://www.readbyqxmd.com/read/28931097/-approaching-new-pharmacotherapy-options-in-pain-treatment
#16
András Telekes
The evolution of medicine is noticeable in most therapeutic areas, the worse the current therapeutic result, the more quick the improvement. This is especially true in such areas that require substantial social resources, namely oncology, diabetology and CNS diseases. Pain is not a disease, it is a symptom. Pain is one of the most important components of human suffering thus it deserves special attention. In recent years new formulations of old medicines were introduced rather than new medicines. Maybe ziconitide is the last pain killer with new mechanism of action which was approved by FDA in 2004...
September 20, 2017: Magyar Onkologia
https://www.readbyqxmd.com/read/28916793/oligodendroglial-excitability-mediated-by-glutamatergic-inputs-and-nav1-2-activation
#17
Emmanuelle Berret, Tara Barron, Jie Xu, Emily Debner, Eun Jung Kim, Jun Hee Kim
Oligodendrocyte (OL) maturation and axon-glial communication are required for proper myelination in the developing brain. However, physiological properties of OLs remain largely uncharacterized in different brain regions. The roles of oligodendroglial voltage-activated Na(+) channels (Nav) and electrical excitability in relation to maturation to the myelinating stage are controversial, although oligodendroglial excitability is potentially important for promoting axon myelination. Here we show spiking properties of OLs and their role in axon-glial communication in the auditory brainstem...
September 15, 2017: Nature Communications
https://www.readbyqxmd.com/read/28905186/antidepressants-inhibit-nav1-3-nav1-7-and-nav1-8-neuronal-voltage-gated-sodium-channels-more-potently-than-nav1-2-and-nav1-6-channels-expressed-in-xenopus-oocytes
#18
Takafumi Horishita, Nobuyuki Yanagihara, Susumu Ueno, Dan Okura, Reiko Horishita, Tomoko Minami, Yuichi Ogata, Yuka Sudo, Yasuhito Uezono, Takeyoshi Sata, Takashi Kawasaki
Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1...
December 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28902151/apetx4-a-novel-sea-anemone-toxin-and-a-modulator-of-the-cancer-relevant-potassium-channel-kv10-1
#19
Lien Moreels, Steve Peigneur, Diogo T Galan, Edwin De Pauw, Lászlo Béress, Etienne Waelkens, Luis A Pardo, Loïc Quinton, Jan Tytgat
The human ether-à-go-go channel (hEag1 or KV10.1) is a cancer-relevant voltage-gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively inhibit this channel can be lead compounds in the search for new anticancer drugs. Here, we report the activity-guided purification and electrophysiological characterization of a novel KV10.1 inhibitor from the sea anemone Anthopleura elegantissima. Purified sea anemone fractions were screened for inhibitory activity on KV10...
September 13, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28882890/c-terminal-phosphorylation-of-nav1-5-impairs-fgf13-dependent-regulation-of-channel-inactivation
#20
Sophie Burel, Fabien C Coyan, Maxime Lorenzini, Matthew R Meyer, Cheryl F Lichti, Joan H Brown, Gildas Loussouarn, Flavien Charpentier, Jeanne M Nerbonne, R Reid Townsend, Lars S Maier, Céline Marionneau
Voltage-gated Na(+) (NaV) channels are key regulators of myocardial excitability, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent alterations in NaV1.5 channel inactivation are emerging as a critical determinant of arrhythmias in heart failure. However, the global native phosphorylation pattern of NaV1.5 subunits associated with these arrhythmogenic disorders and the associated channel regulatory defects remain unknown. Here, we undertook phosphoproteomic analyses to identify and quantify in situ the phosphorylation sites in the NaV1...
October 20, 2017: Journal of Biological Chemistry
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