Ebola: Destroys Na+/K+ Ion Exchange to Accelerate Electrolyte Imbalance by Scorpion Venom-like System

2021 ◽  
Author(s):  
wenzhong liu ◽  
hualan li
Keyword(s):  
Protein Function ◽  
Ebola Virus ◽  
Hemorrhagic Fever ◽  
Scorpion Venom ◽  
Computational Method ◽  
Short Chain ◽  
Electrolyte Imbalance ◽  
Na Channels ◽  
K Channels ◽  
Reverse Mode

Ebola sickness is a hemorrhagic fever caused by the Ebola virus that has an extremely high fatality rate. Electrolyte imbalance is a typical sign in Ebola patients who have already contracted the virus. The use of bioinformatics calculation tools to research Ebola's electrolyte imbalance mechanism is critical for halting the development of the epidemic and saving lives. The computational method of conserved domain search was employed to investigate the protein function of EBOV in this work. This study demonstrates that L, N, S, VP24, and VP35 have LCN type CS-α/β domains. It is a peptide neurotoxin found in scorpions, sea anemone, and snake venom. It can activate Na+ channels and gradually deactivate them, and deactivate voltage- and Ca+2-activated K+ channels. S LCN type CS-α/β is a neurotoxin with a lengthy chain that can activate Na+ channels. VP24, VP35, and N LCN type CS-α/β are short-chain toxins that inhibit voltage-dependent or Ca+2-activated K+ channels and partially inactivate sodium channels. L contains both long- and short-chain LCN type CS-α/β toxins that can activate Na+ channels and inhibit K+ channels. These LCN type CS-α/β can activate Na+ channels and Na+/K+ pumps while simultaneously inactivating K+ channels. It may result in many Na+ entering the cell and a large amount of K+ accumulating within the cell. Simultaneously, the Na+/Ca+ exchange pump outputs Na+ and inputs Ca+2 in “the reverse” mode. The results in an electrolytic environment outside the cell with hyponatremia, hypocalcemia and hypokalemia.

scholarly journals The myth of scorpion suicide: are scorpions insensitive to their own venom?

1998 ◽  
Vol 201 (18) ◽  
pp. 2625-2636
Author(s):  
C Legros ◽  
MF Martin-Eauclaire ◽  
D Cattaert
Keyword(s):  
Action Potential ◽  
Procambarus Clarkii ◽  
Scorpion Venom ◽  
K Channel ◽  
Muscle Fibres ◽  
Channel Blockers ◽  
Na Channels ◽  
Nerve Fibres ◽  
K Channels ◽  
Voltage Gated

The resistance of the scorpion Androctonus australis to its own venom, as well as to the venom of other species, was investigated. A comparison of the electrical and pharmacological properties of muscle and nerve fibres from Androctonus australis with those from the crayfish Procambarus clarkii enabled us to understand the lack of effect of scorpion venom (110-180 microg ml-1) and purified toxins, which are active on voltage-gated Na+ and K+ channels, Ca2+-activated K+ channels, on scorpion tissues. Voltage-clamp experiments showed that peptide K+ channel blockers from scorpion and snake have no effect on currents in muscle and nerve fibres from either scorpions or crayfish. The scorpion toxin kaliotoxin (KTX), a specific blocker of Kv1.1 and Kv1.3 K+ channels, had no effect on muscle fibres of A. australis (2 micromol l-1) or P. clarkii (400 nmol l-1). Similarly, charybdotoxin (ChTX) had no effect on the muscle fibres of A. australis (10 micromol l-1) or P. clarkii (200 nmol l-1) and neither did the snake toxin dendrotoxin (DTX) at concentrations of 100 nmol l-1 in A. australis and 200 nmol l-1 in P. clarkii. These three toxins (KTX, ChTX and DTX) did not block K+ currents recorded from nerve fibres in P. clarkii. The pharmacology of the K+ channels in these two arthropods did not conform to that previously described for K+ channels in other species. Current-clamp experiments clearly indicated that the venom of A. australis (50 microg ml-1) had no effect on the shape of the action potential recorded from nerve cord axons from A. australis. At a concentration of 50 microg ml-1, A. australis venom greatly prolonged the action potential in the crayfish giant axon. The absence of any effect of the anti-mammal <IMG src="/images/symbols/&agr ;.gif" WIDTH="9" HEIGHT="12" ALIGN="BOTTOM" NATURALSIZEFLAG="3">-toxin AaH II (100 nmol l-1) and the anti-insect toxin AaH IT1 (100 nmol l-1) on scorpion nerve fibres revealed strong pharmacological differences between the voltage-gated Na+ channels of scorpion and crayfish. We conclude that the venom from A. australis is pharmacologically inactive on K+ channels and on voltage-sensitive Na+ channels from this scorpion.

Regulation of intracellular calcium in N1E-115 neuroblastoma cells: the role of Na+/Ca2+exchange

2002 ◽  
Vol 282 (5) ◽  
pp. C1000-C1008 ◽  
Author(s):  
Kara L. Kopper ◽  
Joseph S. Adorante
Keyword(s):  
Membrane Potential ◽  
Intracellular Calcium ◽  
Normal Cell ◽  
Buffer Capacity ◽  
Neuroblastoma Cells ◽  
Fold Increase ◽  
Scorpion Venom ◽  
Reverse Mode ◽  
Intracellular Ca

In fura 2-loaded N1E-115 cells, regulation of intracellular Ca2+ concentration ([Ca2+]i) following a Ca2+ load induced by 1 μM thapsigargin and 10 μM carbonylcyanide p-trifluoromethyoxyphenylhydrazone (FCCP) was Na+ dependent and inhibited by 5 mM Ni2+. In cells with normal intracellular Na+ concentration ([Na+]i), removal of bath Na+, which should result in reversal of Na+/Ca2+exchange, did not increase [Ca2+]i unless cell Ca2+ buffer capacity was reduced. When N1E-115 cells were Na+ loaded using 100 μM veratridine and 4 μg/ml scorpion venom, the rate of the reverse mode of the Na+/Ca2+ exchanger was apparently enhanced, since an ∼4- to 6-fold increase in [Ca2+]ioccurred despite normal cell Ca2+ buffering. In SBFI-loaded cells, we were able to demonstrate forward operation of the Na+/Ca2+ exchanger (net efflux of Ca2+) by observing increases (∼ 6 mM) in [Na+]i. These Ni2+ (5 mM)-inhibited increases in [Na+]i could only be observed when a continuous ionomycin-induced influx of Ca2+ occurred. The voltage-sensitive dye bis-(1,3-diethylthiobarbituric acid) trimethine oxonol was used to measure changes in membrane potential. Ionomycin (1 μM) depolarized N1E-115 cells (∼25 mV). This depolarization was Na+dependent and blocked by 5 mM Ni2+ and 250–500 μM benzamil. These data provide evidence for the presence of an electrogenic Na+/Ca2+ exchanger that is capable of regulating [Ca2+]i after release of Ca2+ from cell stores.

Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels

1994 ◽  
Vol 72 (1) ◽  
pp. 349-359 ◽  
Author(s):  
O. Matzner ◽  
M. Devor
Keyword(s):  
Nerve Injury ◽  
Duty Cycle ◽  
Firing Frequency ◽  
Na Channel ◽  
Channel Blockers ◽  
Na Channels ◽  
Experimental Conditions ◽  
K Channels ◽  
Inward Currents ◽  
Ca2 Channels

1. We used the tested fiber method to record from single myelinated afferents axons ending in a chronic nerve injury site (neuroma) in the rat sciatic nerve or L4,5 dorsal root. Axons were chosen for study that fired spontaneously with a stable tonic or interrupted (bursty) autorhythmic firing pattern. 2. Agents that block voltage-sensitive Na+ channels [tetrodotoxin (TTX), lidocaine], voltage-sensitive Ca2+ channels (Cd2+, Co2+, Ni2+, verapamil, D600, nifedipine, and fluarizine), volt-age-sensitive K+ channels [tetraethylammonium (TEA), 4-aminopyridine (4-AP)], and Ca(2+)-activated K+ channels (gK+Ca2+;quinidine, apamine) were applied topically to the neuroma. Effects on baseline rhythmogenesis and on the duty cycle of bursting were documented. Spike pattern analysis was used to determine whether changes in firing frequency were associated with changes in impulse initiation (electrogenesis), or resulted from (partial) block of impulse propagation downstream from the site of electrogenesis. Effects of veratridine were also noted. 3. Na+ channel blockers consistently quenched neuroma firing, and they did so by suppressing the process of impulse initiation. Only rarely was propagation block the dominant process. In bursty fibers the duration of on-periods shortened as the duration of off-periods lengthened, without a significant change in the baseline interspike interval (ISI). Veratridine accelerated firing, also via the impulse generating process. 4. Ca2+ channel blockers had essentially no effect on baseline firing rate (i.e., ISI). 5. Ca2+ channel blockers, as well as blockers of gK+Ca2+, had substantial, but inconsistent effects on burst pattern. It is not clear whether this reflects variability in the experimental conditions, or heterogeneity among the fibers sampled. 6. Blockade of K+ channels failed to evoke rhythmogenesis in acutely cut axons as it does in chronically injured axons, even in the presence of veratridine. This is consistent with other evidence that ectopic neuroma firing depends on postinjury remodeling of membrane electrical properties. 7. The data indicate that, in chronically injured axons, the inward currents that underly electrogenicity, enable ectopic discharge, and, together with outward K+ currents, set the fundamental firing rhythm (ISI), operate primarily with the use of voltage-sensitive Na+ rather than Ca2+ channels. 8. The on-off duty cycle in bursty fibers was affected by Na+ channel ligands and also, although less so, and less consistently by, Ca2+ channel ligands. This indicates that both may play a role in the slow modulations of membrane potential that presumably underly interrupted autorhythmicity.

Ion channels in spinal cord astrocytes in vitro. I. Transient expression of high levels of Na+ and K+ channels

1992 ◽  
Vol 68 (4) ◽  
pp. 985-1000 ◽  
Author(s):  
H. Sontheimer ◽  
J. A. Black ◽  
B. R. Ransom ◽  
S. G. Waxman
Keyword(s):  
Spinal Cord ◽  
Membrane Potentials ◽  
Resting Potential ◽  
K Channel ◽  
Na Channels ◽  
Patch Clamp Recording ◽  
K Channels ◽  
Na Currents ◽  
Channel Expression

1. Na+ and K+ channel expression was studied in cultured astrocytes derived from P--0 rat spinal cord using whole cell patch-clamp recording techniques. Two subtypes of astrocytes, pancake and stellate, were differentiated morphologically. Both astrocyte types showed Na+ channels and up to three forms of K+ channels at certain stages of in vitro development. 2. Both astrocyte types showed pronounced K+ currents immediately after plating. Stellate but not pancake astrocytes additionally showed tetrodotoxin (TTX)-sensitive inward Na+ currents, which displayed properties similar to neuronal Na+ currents. 3. Within 4-5 days in vitro (DIV), pancake astrocytes lost K(+)-current expression almost completely, but acquired Na+ currents in high densities (estimated channel density approximately 2-8 channels/microns2). Na+ channel expression in these astrocytes is approximately 10- to 100-fold higher than previously reported for glial cells. Concomitant with the loss of K+ channels, pancake astrocytes showed significantly depolarized membrane potentials (-28.1 +/- 15.4 mV, mean +/- SD), compared with stellate astrocytes (-62.5 +/- 11.9 mV, mean +/- SD). 4. Pancake astrocytes were capable of generating action-potential (AP)-like responses under current clamp, when clamp potential was more negative than resting potential. Both depolarizing and hyperpolarizing current injections elicited overshooting responses, provided that cells were current clamped to membrane potentials more negative than -70 mV. Anode-break spikes were evoked by large hyperpolarizations (less than -150 mV). AP-like responses in these hyperpolarized astrocytes showed a time course similar to neuronal APs under conditions of low K+ conductance. 5. In stellate astrocytes, AP-like responses were not observed, because the K+ conductance always exceeded Na+ conductance by at least a factor of 3. Thus stellate spinal cord astrocyte membranes are stabilized close to EK as previously reported for hippocampal astrocytes. 6. It is concluded that spinal cord pancake astrocytes are capable of synthesizing Na+ channels at densities that can, under some conditions, support electrogenesis. In vivo, however, AP-like responses are unlikely to occur because the cells' resting potential is too depolarized to allow current activation. Thus the absence of electrogenesis in astrocytes may be explained by two mechanisms: 1) a low Na-to-K conductance ratio, as in stellate spinal cord astrocytes and in other previously studied astrocyte preparations; or, 2) as described in detail in the companion paper, a mismatch between the h infinity curve and resting potential, which results in Na+ current inactivation in spinal cord pancake astrocytes.

scholarly journals Structure of the Ebola virus envelope protein MPER/TM domain and its interaction with the fusion loop explains their fusion activity

2017 ◽  
Vol 114 (38) ◽  
pp. E7987-E7996 ◽  
Author(s):  
Jinwoo Lee ◽  
David A. Nyenhuis ◽  
Elizabeth A. Nelson ◽  
David S. Cafiso ◽  
Judith M. White ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Viral Entry ◽  
Ebola Virus ◽  
Rna Virus ◽  
Hemorrhagic Fever ◽  
Virus Envelope ◽  
Tm Domain ◽  
Virus Envelope Protein ◽  
Niemann Pick ◽  
Fusion Loop

Ebolavirus (EBOV), an enveloped filamentous RNA virus causing severe hemorrhagic fever, enters cells by macropinocytosis and membrane fusion in a late endosomal compartment. Fusion is mediated by the EBOV envelope glycoprotein GP, which consists of subunits GP1 and GP2. GP1 binds to cellular receptors, including Niemann-Pick C1 (NPC1) protein, and GP2 is responsible for low pH-induced membrane fusion. Proteolytic cleavage and NPC1 binding at endosomal pH lead to conformational rearrangements of GP2 that include exposing the hydrophobic fusion loop (FL) for insertion into the cellular target membrane and forming a six-helix bundle structure. Although major portions of the GP2 structure have been solved in pre- and postfusion states and although current models place the transmembrane (TM) and FL domains of GP2 in close proximity at critical steps of membrane fusion, their structures in membrane environments, and especially interactions between them, have not yet been characterized. Here, we present the structure of the membrane proximal external region (MPER) connected to the TM domain: i.e., the missing parts of the EBOV GP2 structure. The structure, solved by solution NMR and EPR spectroscopy in membrane-mimetic environments, consists of a helix-turn-helix architecture that is independent of pH. Moreover, the MPER region is shown to interact in the membrane interface with the previously determined structure of the EBOV FL through several critical aromatic residues. Mutation of aromatic and neighboring residues in both binding partners decreases fusion and viral entry, highlighting the functional importance of the MPER/TM–FL interaction in EBOV entry and fusion.

scholarly journals Annotating proteins with generalized functional linkages

2008 ◽  
Vol 105 (46) ◽  
pp. 17700-17705 ◽  
Author(s):  
Richard Llewellyn ◽  
David S. Eisenberg
Keyword(s):  
Protein Function ◽  
Biological Process ◽  
Computational Method ◽  
Majority Voting ◽  
Target Protein ◽  
Biological Processes ◽  
Gene Products ◽  
Protein Protein Interaction ◽  
Protein Protein Interaction Networks

As genome sequencing outstrips the rate of high-quality, low-throughput biochemical and genetic experimentation, accurate annotation of protein function becomes a bottleneck in the progress of the biomolecular sciences. Most gene products are now annotated by homology, in which an experimentally determined function is applied to a similar sequence. This procedure becomes error-prone between more divergent sequences and can contaminate biomolecular databases. Here, we propose a computational method of assignment of function, termed Generalized Functional Linkages (GFL), that combines nonhomology-based methods with other types of data. Functional linkages describe pairwise relationships between proteins that work together to perform a biological task. GFL provides a Bayesian framework that improves annotation by arbitrating a competition among biological process annotations to best describe the target protein. GFL addresses the unequal strengths of functional linkages among proteins, the quality of existing annotations, and the similarity among them while incorporating available knowledge about the cellular location or individual molecular function of the target protein. We demonstrate GFL with functional linkages defined by an algorithm known as zorch that quantifies connectivity in protein–protein interaction networks. Even when using proteins linked only by indirect or high-throughput interactions, GFL predicts the biological processes of many proteins in Saccharomyces cerevisiae, improving the accuracy of annotation by 20% over majority voting.

scholarly journals Equine-Origin Immunoglobulin Fragments Protect Nonhuman Primates from Ebola Virus Disease

2018 ◽  
Vol 93 (5) ◽  
Author(s):  
Hualei Wang ◽  
Gary Wong ◽  
Wenjun Zhu ◽  
Shihua He ◽  
Yongkun Zhao ◽  
...  
Keyword(s):  
Large Scale ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Disease ◽  
Hemorrhagic Fever ◽  
West African ◽  
Clinical Testing ◽  
The Past ◽  
Over 40 Years

ABSTRACT Ebola virus (EBOV) infections result in aggressive hemorrhagic fever in humans, with fatality rates reaching 90% and with no licensed specific therapeutics to treat ill patients. Advances over the past 5 years have firmly established monoclonal antibody (MAb)-based products as the most promising therapeutics for treating EBOV infections, but production is costly and quantities are limited; therefore, MAbs are not the best candidates for mass use in the case of an epidemic. To address this need, we generated EBOV-specific polyclonal F(ab′)2 fragments from horses hyperimmunized with an EBOV vaccine. The F(ab′)2 was found to potently neutralize West African and Central African EBOV in vitro. Treatment of nonhuman primates (NHPs) with seven doses of 100 mg/kg F(ab′)2 beginning 3 or 5 days postinfection (dpi) resulted in a 100% survival rate. Notably, NHPs for which treatment was initiated at 5 dpi were already highly viremic, with observable signs of EBOV disease, which demonstrated that F(ab′)2 was still effective as a therapeutic agent even in symptomatic subjects. These results show that F(ab′)2 should be advanced for clinical testing in preparation for future EBOV outbreaks and epidemics. IMPORTANCE EBOV is one of the deadliest viruses to humans. It has been over 40 years since EBOV was first reported, but no cure is available. Research breakthroughs over the past 5 years have shown that MAbs constitute an effective therapy for EBOV infections. However, MAbs are expensive and difficult to produce in large amounts and therefore may only play a limited role during an epidemic. A cheaper alternative is required, especially since EBOV is endemic in several third world countries with limited medical resources. Here, we used a standard protocol to produce large amounts of antiserum F(ab′)2 fragments from horses vaccinated with an EBOV vaccine, and we tested the protectiveness in monkeys. We showed that F(ab′)2 was effective in 100% of monkeys even after the animals were visibly ill with EBOV disease. Thus, F(ab′)2 could be a very good option for large-scale treatments of patients and should be advanced to clinical testing.

A point-of-care diagnostic for differentiating Ebola from endemic febrile diseases

2018 ◽  
Vol 10 (471) ◽  
pp. eaat0944 ◽  
Author(s):  
David Sebba ◽  
Alexander G. Lastovich ◽  
Melody Kuroda ◽  
Eric Fallows ◽  
Joshua Johnson ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Clinical Symptoms ◽  
Point Of Care ◽  
Hemorrhagic Fever ◽  
Diagnostic Methods ◽  
Outbreak Detection ◽  
Molecular Diagnostic ◽  
Clinical Samples ◽  
Live Virus ◽  
And Control

Hemorrhagic fever outbreaks such as Ebola are difficult to detect and control because of the lack of low-cost, easily deployable diagnostics and because initial clinical symptoms mimic other endemic diseases such as malaria. Current molecular diagnostic methods such as polymerase chain reaction require trained personnel and laboratory infrastructure, hindering diagnostics at the point of need. Although rapid tests such as lateral flow can be broadly deployed, they are typically not well-suited for differentiating among multiple diseases presenting with similar symptoms. Early detection and control of Ebola outbreaks require simple, easy-to-use assays that can detect and differentiate infection with Ebola virus from other more common febrile diseases. Here, we developed and tested an immunoassay technology that uses surface-enhanced Raman scattering (SERS) tags to simultaneously detect antigens from Ebola, Lassa, and malaria within a single blood sample. Results are provided in <30 min for individual or batched samples. Using 190 clinical samples collected from the 2014 West African Ebola outbreak, along with 163 malaria positives and 233 negative controls, we demonstrated Ebola detection with 90.0% sensitivity and 97.9% specificity and malaria detection with 100.0% sensitivity and 99.6% specificity. These results, along with corresponding live virus and nonhuman primate testing of an Ebola, Lassa, and malaria 3-plex assay, indicate the potential of the SERS technology as an important tool for outbreak detection and clinical triage in low-resource settings.

scholarly journals Ebola Hemorrhagic Fever: Recent Update On Disease Status, Current Therapies And Advances In Treatment

2017 ◽  
Vol 5 (2) ◽  
pp. 217-234
Author(s):  
Jaskaran Singh ◽  
Thapa Komal ◽  
Sandeep Arora ◽  
Amarjot Kaur ◽  
Thakur Gurjeet Singh
Keyword(s):  
Ebola Virus ◽  
Hemorrhagic Fever ◽  
Disease Status ◽  
Clinical Test ◽  
Assessment Development ◽  
Hiv Virus ◽  
The World ◽  
New Guidelines ◽  
Virus Zika ◽  
Grade Methodology

Swiftly growing viruses are a major intimidation to human health. Such viruses are extremely pathogenic like Ebola virus, influenza virus, HIV virus, Zika virus etc . Ebola virus, a type of Filovirus, is an extremely infectious, single-stranded ribonucleic acid virus that infects both humans and apes, prompting acute fever with hemorrhagic syndrome. The high infectivity, severity and mortality of Ebola has plagued the world for the past fifty years with its first outbreak in 1976 in Marburg, Germany, and Frankfurt along with Belgrade and Serbia. The world has perceived about 28,000 cases and over 11,000 losses. The high lethality of Ebola makes it a candidate for use in bioterrorism thereby arising more concern. New guidelines have been framed for providing best possible care to the patients suffering from Ebola virus i.e Grading of Recommendation Assessment, Development And Evaluation (GRADE) methodology to develop evidence-based strategy for the treatment in future outbreak of Ebola virus. No drugs have been approved, while many potent drugs like rVSV-EBOV, Favipiravir, ZMapp are on clinical test for human safety. In this review we will discover and discuss perspective aspects that lead to the evolution of different Ebola variants as well as advances in various drugs and vaccines for treatment of the disease.

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