Neuron Function Inferred From Behavioral And Electrophysiological Extimates Of Refractory Period PdfBy Michel B. In and pdf 27.05.2021 at 10:57 3 min read
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- Artificial Shape Perception Retina Network Based on Tunable Memristive Neurons.
- Absolute refractory period of neurons involved in MFB self-stimulation.
- Revealing neuronal function through microelectrode array recordings
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Artificial Shape Perception Retina Network Based on Tunable Memristive Neurons.
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Clicking on the donut icon will load a page at altmetric. Find more information on the Altmetric Attention Score and how the score is calculated. The tremendous therapeutic potential of voltage-gated sodium channels Na v s has been the subject of many studies in the past and is of intense interest today.
Here we summarize the current status of research in the Na v field and present the most relevant recent developments with respect to the molecular structure, general physiology, and pharmacology of distinct Na v channel subtypes.
We discuss Na v channel ligands such as small molecules, toxins isolated from animal venoms, and the recently identified Na v 1. Finally, we examine possible therapeutic applications of Na v ligands and provide an update on current clinical studies. Figure 1. Na v channel architecture. Each domain contains six transmembrane helical segments S1—6. Plus signs in S4 represent the positively charged voltage sensor containing a number of arginine or lysine residues.
Movement of S6 segments lead to channel opening in response to membrane depolarization. Segments S5, S6, and the connecting pore-loops P-loops form the channel pore. B Extracellular view of the open-channel conformation crystal structure of Na v Ms, a marine bacteria from Magnetococcus sp.
C Side view of the open-channel conformation crystal structure of bacterial Na v Ms. Figure 2. Tissue expression of Na v subtypes and effects of Na v dysfunction on physiology. Figure 3. Toxins isolated from animal venoms that act on Na v channels. A Tetrodotoxin TTX, 1 extracted from the puffer fish.
Figure 4. B,C An extracellular and side view, respectively, of the crystal structure of bacterial Na v Ms. Figure 5. A Amino acid residues known to bind nonselective local anesthetics are conserved among Na v subtypes and are highlighted in blue.
Figure 8. Na v s are very complex molecular structures that rapidly transition through different states closed, open, or inactivated. Ligand binding and functional activity often depends on the conformational state of the channel state dependence , which makes the assessment of structure—activity relationships challenging. The high degree of amino acid sequence homology among the different Na v subtypes makes identifying or designing subtype-selective ligands extremely difficult.
Some Na v ligands show potency differences across animal species, which can complicate the assessment of efficacy in preclinical in vivo models and the design of safety studies. Manuel de Lera Ruiz received his B. After completion of his Ph. Richard L. Kraus received his Ph. We thank Dr. Christopher Burgey, Dr. Joseph Duffy, Dr. Andrea Houghton, Dr. Mark Layton, and Dr. Cameron Cowden for their constructive comments and suggestions.
Editing support from Philippa Solomon is greatly acknowledged. We also thank Dr. Jaume Balsells-Padros for all his encouraging support to put this manuscript together. View Author Information. Cite this: J. ACS AuthorChoice. Article Views Altmetric -. Citations Abstract High Resolution Image. Voltage-gated ion channels VGICs are transmembrane proteins that play important roles in the electrical signaling of cells.
The activity of VGICs is regulated by the membrane potential of a cell, and open channels allow the movement of ions along an electrochemical gradient across cellular membranes. Depending on the ions conducted, VGICs can be classified as voltage-gated sodium, 1 potassium, calcium, or chloride channels.
Voltage-gated sodium currents were discovered by Hodgkin and Huxley in when studying the electric conductance in axons of giant squids. A novel family of Na v 2 channels was discovered recently, however, little is known about its function. In contrast, prokaryotic Na v channels that have been used to explore the structure of eukaryotic Na v s are formed by homotetramers.
In primary sensory neurons, for example, the depolarization of an axon by a noxious stimulus leads to the transmission of sensory information through the nervous system to the brain which may be perceived as pain. In skeletal and cardiac muscle cells, received action potentials produce muscle contraction enabling body movements and blood flow. Interestingly, Na v channels are the molecular targets for a broad range of natural neurotoxins such as tetrodotoxin TTX, 1 , Figures 3 A and 6 , saxitoxin STX, 2 , Figure 6 , and batrachotoxin BTX, 11 , Figures 3 B and 8 as well as peptide toxins isolated from the venoms of scorpions, spiders, sea anemones, and cone snails such as those in Figures 3 C—F.
Those toxins interact with at least six known receptor sites, named Site 1—6, and inhibit or modulate the gating properties of Na v channels. All Na v subtypes known to date can be classified by their sensitivity to the guanidine-based neurotoxin TTX, a toxin isolated from the puffer fish.
Na v channels are very dynamic structures. There are three primary states for Na v channels: a closed resting state, an open conducting state, and a nonconducting inactivated state.
Many known natural and synthetic Na v ligands display different affinities to distinct ion channel states, a phenomenon called state dependence. In contrast, other ion channel modulators show little preference for a particular channel state in their interactions and are considered state-independent modulators. The role of Na v channels in neuronal and cardiac disorders has long been known, and nonselective sodium channel blockers have been developed as anticonvulsant, antiarrhythmic, and local anesthetic drugs in the past.
More recently, mutations in human genes encoding Na v channel subtypes have been linked to channelopathies such as epilepsy, cardiac arrhythmias, and chronic pain syndromes.
The analysis of numerous gain and loss of function mutations have revealed invaluable information about the physiological role of Na v channels in disease. Currently, enormous efforts are underway to find and study the effects of subtype-selective Na v ligands in preclinical disease models and eventually in the clinic.
The wealth of publications and patents in recent years reflects the high interest in this research field. In , approximately articles on Na v s were published, followed by a further in Among these, approximately articles on the Na v 1. In addition, we will discuss the current status of the most significant natural, semisynthetic, and artificial ligands of Na v channels and provide an update on recent clinical developments.
Molecular Architecture. Just over 30 years ago, Catterall, Beneski, and Hartshorne proposed the basic structure of Na v channels based on covalently labeling protein components of purified rat brain Na v s with a photoactive derivative of a scorpion toxin. Of paramount importance is the complete sequencing of the human genome, which has provided us with the identification of ion channel proteins.
Numerous studies using prokaryotic Na v channels have provided us with insight into the structure and function of bacterial Na v channels, translatable to eukaryotic Na v channels. In contrast, prokaryotic Na v channels are far simpler, consisting of homotetramers of four identical polypeptide chains.
Each polypeptide chain contains six transmembrane segments S1—S6 and exhibits high sequence homology when compared to eukaryotic domains.
High Resolution Image. The flexibility of the VSD is primarily mediated by movement of positively charged arginine and lysine residues positioned at every third residue within each S4 helix. The four voltage-sensing domains are arranged around a central aqueous channel formed by the pore domain PD. Upon depolarization, the positively charged S4 transmembrane segments are believed to move toward the extracellular surface.
This motion is transferred to the pore domain via intracellular linkers, causing a conformational change that results in the opening of the channel pore. During depolarization, the channel inactivates as the inactivation gate vide infra folds into the channel pore.
Upon membrane repolarization, Na v channels recover from inactivation and the S4 segments return to their resting positions, becoming available for the next depolarization. From a study of the functional contributions of the amino acid residues at the VSD of skeletal muscle channel subtype Na v 1. This study showed that, surprisingly, not all of the four S1—S4 structures contributing to the VSD adopt the same structural conformation at a specific Na v channel state.
Segments S5, S6, and the extracellular connecting pore-loops P-loops form the channel pore and the selectivity filter SF. As will be discussed later in this review, most Na v -blocking drugs bind to residues at the central water-filled cavity of the pore. Recent structural Na v studies have revealed the existence of additional lateral lipid-filled openings, called fenestrations, connecting the exterior of the channel protein with the central pore.
Na v channel fenestrations could create pathways for small hydrophobic Na v blockers to access the pore from the side through the membrane. Kaczmarski and Corry have investigated Na v subtype specific factors contributing to the size and dynamics of Na v channel fenestrations using MDS and several bacterial and eukaryotic Na v models.
Surprisingly, the structure also has an outer ion site in the selectivity filter vide infra that suggests the presence of multiple ion-binding sites and the possibility that various ions may occupy the selectivity filter simultaneously.
The PD includes the selectivity filter SF, Figure 1 C , the narrowest part of the pore that distinguish ions with similar charges and radii. This is due to the fact that the conformations of the functional groups of the amino acids that constitute the SF are not identical, adopting an asymmetric tetramer. This observation suggests that a similar asymmetric phenomena may occur in eukaryotic counterparts where the level of asymmetry between the four domains is higher.
Absolute refractory period of neurons involved in MFB self-stimulation.
Jellyfish nerve nets provide insight into the origins of nervous systems, as both their taxonomic position and their evolutionary age imply that jellyfish resemble some of the earliest neuron-bearing, actively-swimming animals. Here, we develop the first neuronal network model for the nerve nets of jellyfish. Specifically, we focus on the moon jelly Aurelia aurita and the control of its energy-efficient swimming motion. The proposed single neuron model disentangles the contributions of different currents to a spike. The network model identifies factors ensuring non-pathological activity and suggests an optimization for the transmission of signals.
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Revealing neuronal function through microelectrode array recordings
Relay cells are prevalent throughout sensory systems and receive two types of inputs: driving and modulating. The driving input contains receptive field properties that must be transmitted while the modulating input alters the specifics of transmission. For example, the visual thalamus contains relay neurons that receive driving inputs from the retina that encode a visual image, and modulating inputs from reticular activating system and layer 6 of visual cortex that control what aspects of the image will be relayed back to visual cortex for perception. What gets relayed depends on several factors such as attentional demands and a subject's goals.
Хорошо бы помедленнее. Беккеру не хотелось так быстро уходить от алтаря, но когда две тысячи людей ждут причастия, а обслуживают их всего восемь священнослужителей, было бы неприличным медлить с этим священным глотком. Чаша была уже совсем близко, когда Халохот заметил человека в пиджаке и брюках разного цвета.
Да и краска вонючая. Беккер посмотрел внимательнее.
Разница равна трем. Он медленно потянул к себе микрофон. В то же самое мгновение Сьюзан опять бросила взгляд на руку Танкадо, на этот раз посмотрев не на кольцо… не на гравировку на золоте, а на… его пальцы. Три пальца.
Из задумчивости Стратмора вывел звонок мобильного телефона, едва слышный в завывании сирен и свисте пара. Не останавливаясь, он отстегнул телефон от брючного ремня. - Говорите. - Где мой ключ? - прозвучал знакомый голос. - Кто со мной говорит? - крикнул Стратмор, стараясь перекрыть шум.
Ни у кого не вызывало сомнений, что Стратмор любит свою страну.