scholarly journals Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications

2020 ◽  
Vol 21 (16) ◽  
pp. 5807 ◽  
Author(s):  
Konstantinos Farsalinos ◽  
Elias Eliopoulos ◽  
Demetres D. Leonidas ◽  
Georgios E. Papadopoulos ◽  
Socrates Tzartos ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Extracellular Domain ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Toxin Binding ◽  
Therapeutic Value ◽  
The Many ◽  
Low Prevalence

While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine other potential interactions between the virus and other cell receptors. Based on the clinical observation of low prevalence of smoking among hospitalized COVID-19 patients, we examined and identified a “toxin-like” amino acid (aa) sequence in the Receptor Binding Domain of the Spike Glycoprotein of SARS-CoV-2 (aa 375–390), which is homologous to a sequence of the Neurotoxin homolog NL1, one of the many snake venom toxins that are known to interact with nicotinic acetylcholine receptors (nAChRs). We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein and the superposition of the modelled structure of the Neurotoxin homolog NL1 and the SARS-CoV-2 Spike Glycoprotein. We also performed computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 Spike Glycoprotein and the extracellular domain of the nAChR α9 subunit. We identified a main interaction between the aa 381–386 of the SARS-CoV-2 Spike Glycoprotein and the aa 189–192 of the extracellular domain of the nAChR α9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the α9 nAChR and α-bungarotoxin. A similar interaction was observed between the pentameric α7 AChR chimera and SARS-CoV-2 Spike Glycoprotein. The findings raise the possibility that SARS-CoV-2 may interact with nAChRs, supporting the hypothesis of dysregulation of the nicotinic cholinergic system being implicated in the pathophysiology of COVID-19. Nicotine and other nicotinic cholinergic agonists may protect nAChRs and thus have therapeutic value in COVID-19 patients.

scholarly journals Molecular Modelling and Docking Experiments Examining the Interaction between SARS-CoV-2 Spike Glycoprotein and Neuronal Nicotinic Acetylcholine Receptors

2020 ◽  
Author(s):  
Konstantinos Farsalinos ◽  
Elias Eliopoulos ◽  
Demetres Leonidas ◽  
Georgios Papadopoulos ◽  
Socrates Tzartos ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Molecular Modelling ◽  
Acetylcholine Receptors ◽  
Extracellular Domain ◽  
Spike Glycoprotein ◽  
Nicotinic Acetylcholine ◽  
Venom Toxin ◽  
Toxin Binding ◽  
Snake Venom Toxin ◽  
Alpha Bungarotoxin

While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine for other potential interactions between the virus and other cell receptors. Based on the clinical observation of low smoking prevalence among hospitalized COVID-19 patients, we recently identified a “toxin-like” amino acid (aa) sequence on the receptor binding domain of the spike glycoprotein of SARS-CoV-2 (aa 375-390) with homology to a sequence of a snake venom toxin, which could interact with nicotinic acetylcholine receptors (nAChRs). We now present computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 spike glycoprotein and the extracellular domain of the nAChR alpha9 subunit. We identified an interaction between the aa381-386 of the SARS-CoV-2 spike glycoprotein and the aa189-192 of the extracellular domain of the nAChR alpha9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the alpha9 nAChR and alpha-bungarotoxin. A similar interaction was observed between the pentameric alpha7 AChR and the SARS-CoV-2 spike glycoprotein. Our findings support the hypothesis that severe COVID-19 may be associated with disruption of the nicotinic cholinergic system which could be caused by an interaction between SARS-CoV-2 and nAChRs.

scholarly journals Nicotinic Cholinergic System and COVID-19: Identification of a Potentially Crucial Snake Toxin-Like Sequence in the SARS-CoV-2 Spike Glycoprotein

2020 ◽  
Author(s):  
Konstantinos Farsalinos ◽  
Elias Eliopoulos ◽  
Socrates Tzartos ◽  
Konstantinos Poulas
Keyword(s):  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Respiratory Infections ◽  
Clinical Manifestations ◽  
Case Series ◽  
Spike Glycoprotein ◽  
Venom Toxin ◽  
Snake Venom Toxin ◽  
Low Prevalence ◽  
Viral Cell Entry

Smoking is a risk factor for respiratory infections and there is reasonable concern that it may affect COVID-19 susceptibility and severity. Recent studies have focused on the interaction between smoking (and nicotine) and ACE2 expression, suggesting that ACE2 up-regulation could contribute to enhanced viral cell entry. However, case series have shown that there is an unexpectedly low prevalence of smoking among hospitalized COVID-19 cases. Since early April, we were the first to hypothesize that dysfunction of the nicotinic cholinergic system (NCS) may be implicated in the pathophysiology of severe COVID-19. We recently reported that many of the clinical manifestations of severe COVID-19 could be explained by dysregulation of the NCS. In this study, we present an amino acid sequence in the receptor binding domain of the SARS-CoV-2 Spike glycoprotein which is homologous to a sequence of a snake venom toxin. We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein. These findings suggest that SARS-CoV-2 could potentially interact with acetylcholine receptors causing dysregulation of the NCS and the cholinergic anti-inflammatory pathway.

scholarly journals Disorders of the Cholinergic System in COVID-19 Era—A Review of the Latest Research

2022 ◽  
Vol 23 (2) ◽  
pp. 672
Author(s):  
Marta Kopańska ◽  
Marta Batoryna ◽  
Paulina Bartman ◽  
Jacek Szczygielski ◽  
Agnieszka Banaś-Ząbczyk
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Cytokine Production ◽  
Negative Influence ◽  
Antiviral Drugs ◽  
Angiotensin Converting Enzyme 2 ◽  
Non Invasive

The appearance of the SARS-CoV-2 virus initiated many studies on the effects of the virus on the human body. So far, its negative influence on the functioning of many morphological and physiological units, including the nervous system, has been demonstrated. Consequently, research has been conducted on the changes that SARS-CoV-2 may cause in the cholinergic system. The aim of this study is to review the latest research from the years 2020/2021 regarding disorders in the cholinergic system caused by the SARS-CoV-2 virus. As a result of the research, it was found that the presence of the COVID-19 virus disrupts the activity of the cholinergic system, for example, causing the development of myasthenia gravis or a change in acetylcholine activity. The SARS-CoV-2 spike protein has a sequence similar to neurotoxins, capable of binding nicotinic acetylcholine receptors (nAChR). This may be proof that SARS-CoV-2 can bind nAChR. Nicotine and caffeine have similar structures to antiviral drugs, capable of binding angiotensin-converting enzyme 2 (ACE 2) epitopes that are recognized by SARS-CoV-2, with the potential to inhibit the formation of the ACE 2/SARS-CoV-2 complex. The blocking is enhanced when nicotine and caffeine are used together with antiviral drugs. This is proof that nAChR agonists can be used along with antiviral drugs in COVID-19 therapy. As a result, it is possible to develop COVID-19 therapies that use these compounds to reduce cytokine production. Another promising therapy is non-invasive stimulation of the vagus nerve, which soothes the body’s cytokine storm. Research on the influence of COVID-19 on the cholinergic system is an area that should continue to be developed as there is a need for further research. It can be firmly stated that COVID-19 causes a dysregulation of the cholinergic system, which leads to a need for further research, because there are many promising therapies that will prevent the SARS-CoV-2 virus from binding to the nicotinic receptor. There is a need for further research, both in vitro and in vivo. It should be noted that in the functioning of the cholinergic system and its connection with the activity of the COVID-19 virus, there might be many promising dependencies and solutions.

Aluminum Suppresses Effect of Nicotine on Gamma Oscillations (20-40 Hz) in Mouse Hippocampal Slices

2018 ◽  
Vol 17 (6) ◽  
pp. 404-411 ◽  
Author(s):  
Syeda Mehpara Farhat ◽  
Touqeer Ahmed
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Peak Power ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Gamma Oscillations ◽  
Gamma Oscillation ◽  
Facilitatory Effect

Background: Aluminum (Al) causes neurodegeneration and its toxic effects on cholinergic system in the brain is well documented. However, it is unknown whether and how Al changes oscillation patterns, driven by the cholinergic system, in the hippocampus. Objective: We studied acute effects of Al on nicotinic acetylcholine receptors (nAChRs)-mediated modulation of persistent gamma oscillations in the hippocampus. Method: The field potential recording was done in CA3 area of acute hippocampal slices. Results: Carbachol-induced gamma oscillation peak power increased (1.32±0.09mV2/Hz, P<0.01) in control conditions (without Al) by application of 10µM nicotine as compared to baseline value normalized to 1. This nicotine-induced facilitation of gamma oscillation peak power was found to depend on non-α7 nAChRs. In slices with Al pre-incubation for three to four hours, gamma oscillation peak power was reduced (5.4±1.8mV2/Hz, P<0.05) and facilitatory effect of nicotine on gamma oscillation peak power was blocked as compared to the control (18.06±2.1mV2/Hz) or one hour Al pre-incubated slices (11.3±2.5mV2/Hz). Intriguingly wash-out, after three to four hours of Al incubation, failed to restore baseline oscillation power and its facilitation by nicotine as no difference was observed in gamma oscillation peak power between Al wash-out slices (3.4±1.1mV2/Hz) and slices without washout (3.6±0.9mV2/Hz). Conclusion: This study shows that at cellular level, exposure of hippocampal tissue to Al compromised nAChR-mediated facilitation of cholinergic hippocampal gamma oscillations. Longer in vitro Al exposure caused permanent changes in hippocampal oscillogenic circuitry and changed its sensitivity to nAChR-modulation. This study will help to understand the possible mechanism of cognitive decline induced by Al.

Human Nicotinic Acetylcholine Receptors: Part II. Non-Neuronal Cholinergic System

2019 ◽  
Vol 45 (2) ◽  
pp. 66-75 ◽  
Author(s):  
M. A. Shulepko ◽  
D. S. Kulbatskii ◽  
M. L. Bychkov ◽  
E. N. Lyukmanova
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine

scholarly journals Mechanisms of Coupling between Angiotensin Converting Enzyme 2 and Nicotinic Acetylcholine Receptors

2021 ◽  
Author(s):  
Nadine Kabbani ◽  
Kyle Brumfield ◽  
Patricia Sinclair ◽  
Arvind Ramanathan ◽  
Rita Colwell ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Sequence Similarity ◽  
Physical Interaction ◽  
Converting Enzyme ◽  
Structural Protein ◽  
Nicotinic Acetylcholine ◽  
Susceptible Host ◽  
Angiotensin Converting Enzyme 2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus encapsulated by a spike (S) glycoprotein envelope, binds with high affinity to angiotensin converting enzyme 2 (ACE2) during cell entry of a susceptible host. Recent studies suggest nicotinic acetylcholine receptors (nAChRs) play a role in functional ACE2 regulation and nicotine may contribute to the progression of coronavirus disease 2019 (COVID-19). Here, we present evidence for coupling between ACE2 and nAChR through bioinformatic analysis and cell culture experiments. Following molecular and structural protein comparison of over 250 ACE2 vertebrate orthologues, a region of human ACE2 at positions C542-L554 was identified to have sequence similarity to nAChR-binding neurotoxin and rabies virus glycoproteins (RBVG). Furthermore, experiments conducted in PC12 cells indicate a potential for physical interaction between ACE2 and alpha 7 nAChR proteins. Our findings support a model of nAChR involvement in in COVID-19.

scholarly journals Neural circuits and nicotinic acetylcholine receptors mediate the cholinergic regulation of midbrain dopaminergic neurons and nicotine dependence

2019 ◽  
Vol 41 (1) ◽  
pp. 1-9 ◽  
Author(s):  
Cheng Xiao ◽  
Chun-yi Zhou ◽  
Jin-hong Jiang ◽  
Cui Yin
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Cholinergic System ◽  
Acetylcholine Receptors ◽  
Drug Targets ◽  
Clinical Investigation ◽  
Nicotinic Acetylcholine ◽  
Smoking Intervention ◽  
Cholinergic Regulation ◽  
Midbrain Dopaminergic Neurons ◽  
Activity Dependent

Abstract Midbrain dopaminergic (DA) neurons are governed by an endogenous cholinergic system, originated in the mesopontine nuclei. Nicotine hijacks nicotinic acetylcholine receptors (nAChRs) and interferes with physiological function of the cholinergic system. In this review, we describe the anatomical organization of the cholinergic system and the key nAChR subtypes mediating cholinergic regulation of DA transmission and nicotine reward and dependence, in an effort to identify potential targets for smoking intervention. Cholinergic modulation of midbrain DA systems relies on topographic organization of mesopontine cholinergic projections, and activation of nAChRs in midbrain DA neurons. Previous studies have revealed that α4, α6, and β2 subunit-containing nAChRs expressed in midbrain DA neurons and their terminals in the striatum regulate firings of midbrain DA neurons and activity-dependent dopamine release in the striatum. These nAChRs undergo modification upon chronic nicotine exposure. Clinical investigation has demonstrated that partial agonists of these receptors elevate the success rate of smoking cessation relative to placebo. However, further investigations are required to refine the drug targets to mitigate unpleasant side-effects.

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