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1.
Int J Biochem Cell Biol ; 143: 106138, 2022 02.
Article in English | MEDLINE | ID: covidwho-1588223

ABSTRACT

Nicotinic acetylcholine receptors mediate fast synaptic transmission in neuro-muscular junctions and autonomic ganglia and modulate survival, proliferation and neurotransmitter or cytokine release in the brain and non-excitable cells. The neuronal-type nicotinic acetylcholine receptors are expressed in the outer mitochondria membrane to regulate the release of pro-apoptotic substances like cytochrome c or reactive oxygen species. In the intracellular environment, nicotinic acetylcholine receptor signaling is ion-independent and triggers intramitochondrial kinases, similar to those activated by plasma membrane nicotinic acetylcholine receptors. The present review will describe the data obtained during the last five years including, in particular, post-translational glycosylation as a targeting signal to mitochondria, mechanisms of mitochondrial nicotinic acetylcholine receptor signaling studied with subtype-specific agonists, antagonists, positive allosteric modulators and knockout mice lacking certain nicotinic acetylcholine receptor subunits, interaction of mitochondrial nicotinic acetylcholine receptors with Bcl-2 family proteins and their involvement in important pathologies like neuroinflammation, liver damage and SARS-CoV-2 infection.


Subject(s)
COVID-19/genetics , Chemical and Drug Induced Liver Injury/genetics , Mitochondria/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Receptors, Nicotinic/genetics , Allosteric Regulation , Animals , COVID-19/metabolism , COVID-19/pathology , COVID-19/virology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Humans , Mice , Mitochondria/metabolism , /pathology , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Protein Processing, Post-Translational , Proto-Oncogene Proteins c-bcl-2/metabolism , Receptors, Nicotinic/metabolism , SARS-CoV-2/pathogenicity , Signal Transduction , Voltage-Dependent Anion Channel 1/genetics , Voltage-Dependent Anion Channel 1/metabolism
2.
Environ Toxicol Pharmacol ; 86: 103656, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1171468

ABSTRACT

Evidence in humans suggests a correlation between nicotine smoking and severe respiratory symptoms with COVID-19 infection. In lung tissue, angiotensin-converting enzyme 2 (ACE2) appears to mechanistically underlie viral entry. Here, we investigated whether e-cigarette vapor inhalation alters ACE2 and nicotinic acetylcholine receptor (nAChR) expression in male and female mice. In male lung, nicotine vapor inhalation induced a significant increase in ACE2 mRNA and protein, but surprisingly, these differences were not found in females. Further, both vehicle and nicotine vapor inhalation downregulated α5 nAChR subunits in both sexes, while differences were not found in α7 nAChR subunit expression. Finally, blood ACE2 levels did not differ with exposure, indicating that blood sampling is not a sufficient indicator of lung ACE2 changes. Together, these data indicate a direct link between e-cigarette vaping and increased ACE2 expression in male lung tissue, which thereby reveals an underlying mechanism of increased vulnerability to coronavirus infection in individuals vaping nicotine.


Subject(s)
Angiotensin-Converting Enzyme 2/biosynthesis , COVID-19/epidemiology , Electronic Nicotine Delivery Systems , Lung/enzymology , Vaping/adverse effects , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/genetics , Animals , DNA, Complementary/biosynthesis , Female , Lung/cytology , Male , Mice , Mice, Inbred C57BL , Nicotine/administration & dosage , Nicotine/pharmacology , Nicotinic Agonists/administration & dosage , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/biosynthesis , Sex Characteristics , alpha7 Nicotinic Acetylcholine Receptor/metabolism
3.
Cell Biol Int ; 45(7): 1533-1545, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1141294

ABSTRACT

Polymorphonuclear neutrophilic granulocytes (PMNs) are the largest proportion of leukocytes in adult human blood that perform numerous functions, including phagocytosis, degranulation, generation of reactive oxygen species, and NETosis. Excessive neutrophil activity associates with hyperinflammation and tissue damage during pathologies such as inflammatory bowel disease, diabetes mellitus, tuberculosis, and coronavirus disease 2019. Nicotinic acetylcholine receptors (nAChRs) can modulate immune cells, including neutrophils, functions, therefore, nAChR ligands are considered as the potent agents for therapy of inflammation. Earlier it was shown, that about 30% of PMNs from the acute inflammatory site responded to nicotine by calcium spikes. In this study, we studied the generation of calcium spikes in murine granulocytes with different maturity level (evaluated by Gr-1 expression) isolated from bone marrow in response to ligands of nAChRs in control and under chronic nicotine consumption. It was found that nearly 20%-25% cells in the granulocyte population responded to nicotine or selective antagonists of different type of nAChRs (α-cobratoxin, GIC, and Vc1.1). We demonstrated that in the control group Ca2+ -mobilizing activity was regulated through α7 and α9α10 nAChRs in immature granulocytes (Gr-1int ), whereas in mature granulocytes (Gr-1hi ) it was regulated through α7, α3ß2, and α9-contained nAChRs. Sensitivity of PMNs to nicotine depended on their maturity level after chronic nicotine consumption. Gr-1int cells responded to nicotine through α7 and α9-contained nAChRs, while Gr-1hi did not respond to nicotine. Thus, calcium response to nAChR ligands in bone marrow PMNs depends on their maturity level.


Subject(s)
Antigens, Ly/metabolism , Bone Marrow Cells/drug effects , Calcium Signaling/drug effects , Calcium/metabolism , Cholinergic Agents/pharmacology , Granulocytes/drug effects , Receptors, Nicotinic/drug effects , Animals , Bone Marrow Cells/metabolism , Cells, Cultured , Granulocytes/metabolism , Ligands , Male , Mice, Inbred BALB C , Nicotine/pharmacology , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Receptors, Nicotinic/metabolism
4.
Mol Med ; 26(1): 63, 2020 06 29.
Article in English | MEDLINE | ID: covidwho-617382

ABSTRACT

BACKGROUND: Oxygen therapy, using supraphysiological concentrations of oxygen (hyperoxia), is routinely administered to patients who require respiratory support including mechanical ventilation (MV). However, prolonged exposure to hyperoxia results in acute lung injury (ALI) and accumulation of high mobility group box 1 (HMGB1) in the airways. We previously showed that airway HMGB1 mediates hyperoxia-induced lung injury in a mouse model of ALI. Cholinergic signaling through the α7 nicotinic acetylcholine receptor (α7nAChR) attenuates several inflammatory conditions. The aim of this study was to determine whether 3-(2,4 dimethoxy-benzylidene)-anabaseine dihydrochloride, GTS-21, an α7nAChR partial agonist, inhibits hyperoxia-induced HMGB1 accumulation in the airways and circulation, and consequently attenuates inflammatory lung injury. METHODS: Mice were exposed to hyperoxia (≥99% O2) for 3 days and treated concurrently with GTS-21 (0.04, 0.4 and 4 mg/kg, i.p.) or the control vehicle, saline. RESULTS: The systemic administration of GTS-21 (4 mg/kg) significantly decreased levels of HMGB1 in the airways and the serum. Moreover, GTS-21 (4 mg/kg) significantly reduced hyperoxia-induced acute inflammatory lung injury, as indicated by the decreased total protein content in the airways, reduced infiltration of inflammatory monocytes/macrophages and neutrophils into the lung tissue and airways, and improved lung injury histopathology. CONCLUSIONS: Our results indicate that GTS-21 can attenuate hyperoxia-induced ALI by inhibiting extracellular HMGB1-mediated inflammatory responses. This suggests that the α7nAChR represents a potential pharmacological target for the treatment regimen of oxidative inflammatory lung injury in patients receiving oxygen therapy.


Subject(s)
Acute Lung Injury/etiology , Acute Lung Injury/metabolism , Benzylidene Compounds/pharmacology , HMGB1 Protein/metabolism , Hyperoxia/complications , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Animals , Biomarkers , Disease Susceptibility , HMGB1 Protein/blood , HMGB1 Protein/genetics , Immunohistochemistry , Male , Mice , Models, Biological
5.
Neurochem Int ; 138: 104779, 2020 09.
Article in English | MEDLINE | ID: covidwho-436706

ABSTRACT

The brain nicotinic acetylcholine receptors (nAChRs) expressed in pre-synaptic nerve terminals regulate neurotransmitter release. However, there is no evidence for the expression of nAChRs in synaptic vesicles, which deliver neurotransmitter to synaptic cleft. The aim of this paper was to investigate the presence of nAChRs in synaptic vesicles purified from the rat brain and to study their possible involvement in vesicles life cycle. According to dynamic light scattering analysis, the antibody against extracellular domain (1-208) of α7 nAChR subunit inhibited synaptic vesicles clustering. Sandwich ELISA with nAChR subunit-specific antibodies demonstrated the presence of α4ß2, α7 and α7ß2nAChR subtypes in synaptic vesicles and showed that α7 and ß2 nAChR subunits are co-localized with synaptic vesicle glycoprotein 2A (SV2A). Pre-incubation with either α7-selective agonist PNU282987 or nicotine did not affect synaptic vesicles clustering but delayed their Ca2+-dependent fusion with the plasma membranes. In contrast, nicotine but not PNU282987 stimulated acidification of isolated synaptic vesicles, indicating that α4ß2 but not α7-containing nAChRs are involved in regulation of proton influx and neurotransmitter refilling. Treatment of rats with levetiracetam, a specific modulator of SV2A, increased the content of α7 nAChRs in synaptic vesicles accompanied by increased clustering but decreased Ca2+-dependent fusion. These data for the first time demonstrate the presence of nAChRs in synaptic vesicles and suggest an active involvement of cholinergic regulation in neurotransmitter release. Synaptic vesicles may be an additional target of nicotine inhaled upon smoking and of α7-specific drugs widely discussed as anti-inflammatory and pro-cognitive tools.


Subject(s)
Brain/metabolism , Cell Membrane/metabolism , Membrane Fusion/physiology , Synaptic Vesicles/metabolism , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Brain/drug effects , Cell Membrane/drug effects , Female , Hydrogen-Ion Concentration , Male , Membrane Fusion/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Nicotinic Agonists/pharmacology , Nicotinic Antagonists/pharmacology , Rats , Rats, Wistar , Synaptic Vesicles/drug effects , alpha7 Nicotinic Acetylcholine Receptor/agonists , alpha7 Nicotinic Acetylcholine Receptor/antagonists & inhibitors
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