nAChRs Dotaz Zobrazit nápovědu
OBJECTIVES: Our previous study showed that administration of nicotine is capable to protect the neurons of hippocampus against the kainic acid induced damage. Here we tested the hypotheses that multiple nicotine administration would prevent the effects of kainic acid on neuronal nicotinic receptor subtypes densities (α-bungarotoxin sensitive and α-bungarotoxin insentive) and on hippocampal cell degeneration. METHODS: Radioligand binding study was used to detect the particular nAChR subtypes densities. Two histochemical methods (bis-benzimide staining and Fluoro-Jade B dye) were used to detect and evaluate neuronal degeneration. RESULTS: Our study shows that: a) kainic acid single administration increased the number of α-bungarotoxin insentive nicotinic receptors, b) nicotine was able to prevent such changes, c) repeated nicotine administration is capable to attenuate the damage of CA1 and CA3 areas of the hippocampus. No effect on α-bungarotoxin sentive nicotinic receptors was observed. Our data therefore reveal the importance of α-bungarotoxin insentive nicotinic receptors in the response to kainite and the ability of nicotine to prevent such changes both in the cell degeneration and in number of receptors. CONCLUSION: Nicotine administration influences α-bungarotoxin insensitive receptors and repeated administration is capable to protect against toxicity caused by kainic acid in hippocampal area.
- MeSH
- agonisté excitačních aminokyselin farmakologie MeSH
- bungarotoxiny metabolismus MeSH
- hipokampus cytologie MeSH
- krysa rodu Rattus MeSH
- kyselina kainová farmakologie MeSH
- neurony cytologie účinky léků patologie MeSH
- neuroprotektivní látky farmakologie MeSH
- nikotin farmakologie MeSH
- nikotinové receptory metabolismus MeSH
- nikotinoví agonisté farmakologie MeSH
- potkani Wistar MeSH
- protein - isoformy metabolismus MeSH
- radioligandová zkouška MeSH
- zvířata MeSH
- Check Tag
- krysa rodu Rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- agonisté excitačních aminokyselin MeSH
- bungarotoxiny MeSH
- kyselina kainová MeSH
- neuroprotektivní látky MeSH
- nikotin MeSH
- nikotinové receptory MeSH
- nikotinoví agonisté MeSH
- protein - isoformy MeSH
Acetylcholine is an important modulator of striatal activity, and it is vital to controlling striatal-dependent behaviors, including motor and cognitive functions. Despite this significance, the mechanisms determining how acetylcholine impacts striatal signaling are still not fully understood. In particular, little is known about the role of nAChRs expressed by striatal interneurons. In the present study, we used FISH to determine which neuronal types express the most prevalent beta2 nicotinic subunit in the mouse striatum. Our data support a common view that nAChR expression is mostly restricted to striatal interneurons. Surprisingly though, cholinergic interneurons were identified as a population with the highest expression of beta2 nicotinic subunit. To investigate the functional significance of beta2-containing nAChRs in striatal interneurons, we deleted them by injecting the AAV-Cre vector into the striatum of beta2-flox/flox male mice. The deletion led to alterations in several behavioral domains, namely, to an increased anxiety-like behavior, decrease in sociability ratio, deficit in discrimination learning, and increased amphetamine-induced hyperlocomotion and c-Fos expression in mice with beta2 deletion. Further colocalization analysis showed that the increased c-Fos expression was present in both medium spiny neurons and presumed striatal interneurons. The present study concludes that, despite being relatively rare, beta2-containing nAChRs are primarily expressed in striatal neurons by cholinergic interneurons and play a significant role in behavior.SIGNIFICANCE STATEMENT A large variety of nAChRs are expressed in the striatum, a brain region that is crucial in the control of behavior. The complexity of receptors with different functions is hindering our understanding of mechanisms through which striatal acetylcholine modulates behavior. We focused on the role of a small population of beta2-containing nAChRs. We identified neuronal types expressing these receptors and determined their impact in the control of explorative behavior, anxiety-like behavior, learning, and sensitivity to stimulants. Additional experiments showed that these alterations were associated with an overall increased activity of striatal neurons. Thus, the small population of nicotinic receptors represents an interesting target for a modulation of response to stimulant drugs and other striatal-based behavior.
- Klíčová slova
- Fos, acetylcholine, behavior, interneurons, nAChRs, striatum,
- MeSH
- acetylcholin metabolismus MeSH
- cholinergní látky farmakologie MeSH
- corpus striatum metabolismus MeSH
- interneurony metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nikotinové receptory * metabolismus MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholin MeSH
- cholinergní látky MeSH
- nikotinové receptory * MeSH
Human-secreted Ly-6/uPAR-related protein-2 (SLURP-2) regulates the growth and differentiation of epithelial cells. Previously, the auto/paracrine activity of SLURP-2 was considered to be mediated via its interaction with the α3β2 subtype of the nicotinic acetylcholine receptors (nAChRs). Here, we describe the structure and pharmacology of a recombinant analogue of SLURP-2. Nuclear magnetic resonance spectroscopy revealed a 'three-finger' fold of SLURP-2 with a conserved β-structural core and three protruding loops. Affinity purification using cortical extracts revealed that SLURP-2 could interact with the α3, α4, α5, α7, β2, and β4 nAChR subunits, revealing its broader pharmacological profile. SLURP-2 inhibits acetylcholine-evoked currents at α4β2 and α3β2-nAChRs (IC50 ~0.17 and >3 μM, respectively) expressed in Xenopus oocytes. In contrast, at α7-nAChRs, SLURP-2 significantly enhances acetylcholine-evoked currents at concentrations <1 μM but induces inhibition at higher concentrations. SLURP-2 allosterically interacts with human M1 and M3 muscarinic acetylcholine receptors (mAChRs) that are overexpressed in CHO cells. SLURP-2 was found to promote the proliferation of human oral keratinocytes via interactions with α3β2-nAChRs, while it inhibited cell growth via α7-nAChRs. SLURP-2/mAChRs interactions are also probably involved in the control of keratinocyte growth. Computer modeling revealed possible SLURP-2 binding to the 'classical' orthosteric agonist/antagonist binding sites at α7 and α3β2-nAChRs.
- MeSH
- adaptorové proteiny signální transdukční MeSH
- alfa7 nikotinové acetylcholinové receptory metabolismus MeSH
- buněčné linie MeSH
- buňky PC12 MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- dospělí MeSH
- epilepsie temporálního laloku patologie MeSH
- evokované potenciály fyziologie MeSH
- GPI-vázané proteiny metabolismus MeSH
- keratinocyty metabolismus MeSH
- krysa rodu Rattus MeSH
- lidé středního věku MeSH
- lidé MeSH
- nikotinové receptory metabolismus MeSH
- nukleární magnetická rezonance biomolekulární MeSH
- oocyty metabolismus MeSH
- počítačová simulace MeSH
- proliferace buněk fyziologie MeSH
- receptory muskarinové metabolismus MeSH
- vazba proteinů fyziologie MeSH
- vazebná místa fyziologie MeSH
- Xenopus MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- krysa rodu Rattus MeSH
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- alfa7 nikotinové acetylcholinové receptory MeSH
- GPI-vázané proteiny MeSH
- LYNX1 protein, human MeSH Prohlížeč
- nicotinic receptor alpha3beta2 MeSH Prohlížeč
- nikotinové receptory MeSH
- receptory muskarinové MeSH
BACKGROUND: Stroke is devastating cerebrovascular event which is responsible for 6.7 million deaths each year worldwide. Inflammation plays an important role in the pathophysiology of stroke. Targeting inflammation after stroke is highly actual topic for both experimental and clinical research. METHODS: Research articles related to cholinergic anti-inflammatory pathway (CHAIP) and stroke were reviewed. The first part of review describes the basic characteristics of inflammatory response after stroke, main components and function of CHAIP. The second part reviews studies focused on CHAIP as a therapeutic target for ischemic and hemorrhagic stroke. Both pharmacological stimulation of α7 nAChR and vagus nerve stimulation after stroke are reviewed. RESULTS: Cholinergic anti-inflammatory pathway (CHAIP) is a physiological mechanism by which central nervous system regulates immune response and controls inflammation. Vagus nerve, spleen and α7 nicotinic acetylcholine receptor (α7 nAChR) are the main components of CHAIP. CONCLUSION: Targeting cholinergic anti-inflammatory pathway is a promising way of immunomodulation which attenuates inflammation in a complex manner without causing immunosuppression.
- Klíčová slova
- Cerebral ischemia, Vagus nerve stimulation, cholinergic anti-inflammatory pathway, inflammation, intracerebral hemorrhage, stroke, subarachnoid hemorrhage, α7 nicotinic acetylcholine receptor (α7 nAChR),
- MeSH
- alfa7 nikotinové acetylcholinové receptory fyziologie MeSH
- centrální nervový systém fyziologie MeSH
- cévní mozková příhoda imunologie patofyziologie MeSH
- lidé MeSH
- nervus vagus fyziologie MeSH
- slezina fyziologie MeSH
- zánět patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- alfa7 nikotinové acetylcholinové receptory MeSH
Nicotinic acetylcholine receptors (nAChRs) are widely expressed in the central nervous system and play an important role in the control of neural functions including neuronal activity, transmitter release and synaptic plasticity. Although the common subtypes of nAChRs are abundantly expressed throughout the brain, their expression in different brain regions and by individual neuronal types is not homogeneous or incidental. In recent years, several studies have emerged showing that particular subtypes of nAChRs are expressed by specific neuronal populations in which they have major influence on the activity of local circuits and behavior. It has been demonstrated that even nAChRs expressed by relatively rare neuronal types can induce significant changes in behavior and contribute to pathological processes. Depending on the identity and connectivity of the particular nAChRs-expressing neuronal populations, the activation of nAChRs can have distinct or even opposing effects on local neuronal signaling. In this review, we will summarize the available literature describing the expression of individual nicotinic subunits by different neuronal types in two crucial brain regions, the striatum and the prefrontal cortex. The review will also briefly discuss nicotinic expression in non-neuronal, glial cells, as they cannot be ignored as potential targets of nAChRs-modulating drugs. The final section will discuss options that could allow us to target nAChRs in a neuronal-type-specific manner, not only in the experimental field, but also eventually in clinical practice.
- Klíčová slova
- Cholinergic system, Expression, Interneurons, Nicotinic acetylcholine receptors, Prefrontal cortex, Striatum,
- MeSH
- corpus striatum metabolismus MeSH
- lidé MeSH
- neurony * metabolismus MeSH
- nikotinové receptory * metabolismus MeSH
- prefrontální mozková kůra * metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- nikotinové receptory * MeSH
BACKGROUND: Autoantibodies against nicotinic acetylcholine receptor (nAChR) in myasthenia gravis (MG) patients are usually detected by radioimmunoprecipitation assays using extracted acetylcholine receptors labeled irreversibly with 125I-alpha-bungarotoxin (alpha-BuTx). To provide a nonradioactive immunoassay, we established an assay using nAChRs labeled with Eu(3+)-alpha-cobratoxin (alpha-CTx). METHODS: We derivatized alpha-CTx with a diethylenetriaminepentaacetate moiety and formed a complex with Eu(3+). The complex was purified by HPLC, and the fractions were tested for binding to Torpedo and human nAChRs. The most active fractions were used to label nAChRs for the immunoprecipitation assay, and the bound Eu(3+) was quantified by time-resolved fluorescence. RESULTS: Eu(3+)-labeled alpha-CTx competed with 125I-alpha-BuTx for binding to Torpedo nAChRs and saturated the binding sites of human nAChRs, with a K(d) of 7.2 x 10(-9) mol/L. Results of the immunoassay performed with Eu(3+)-labeled alpha-CTx were similar to those obtained with 125I-alpha-BuTx, with a slightly higher limit of detection [0.3 nmol/L (n = 6) vs approximately 0.1 nmol/L for isotopic assay]. None of 34 negative sera tested (16 healthy controls, 10 patients with nonmyasthenia-related disease, 8 patients seronegative for MG) gave a value >0.3 nmol/L. Of the 35 positive myasthenic sera (with antibody values, previously determined by isotopic assay, of 0.4-1290 nmol/L) compared in the two assays, 32 tested positive with the Eu(3+) assay. Linear regression analysis yielded the equation: y = 1.035x - 0.013 nmol/L; S(y:x) = 0.172 nmol/L; r(2) = 0.977. CONCLUSIONS: The new time-resolved fluorescence method for quantification of antibodies to nAChRs in MG patients provides a performance similar to that of the widely used isotopic assay and could be used in laboratories with restricted use of isotopes.
- MeSH
- autoprotilátky krev MeSH
- dospělí MeSH
- elektrické orgány MeSH
- europium MeSH
- fluoroimunoanalýza MeSH
- kobří neurotoxiny MeSH
- lidé středního věku MeSH
- lidé MeSH
- myasthenia gravis diagnóza MeSH
- nádorové buňky kultivované MeSH
- nikotinové receptory imunologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- Torpedo MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alpha-cobratoxin MeSH Prohlížeč
- autoprotilátky MeSH
- europium MeSH
- kobří neurotoxiny MeSH
- nikotinové receptory MeSH
Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is an important part of the cholinergic nerve system in the brain. Moreover, it is associated with a cholinergic anti-inflammatory pathway in the termination of the parasympathetic nervous system. Antagonists of α7 nAChR are a wide group represented by conotoxin and bungarotoxin. Even Alzheimer's disease drug memantine acting as an antagonist in its side pathway belongs in this group. Agonists of α7 nAChR are suitable for treatment of multiple cognitive dysfunctions such as Alzheimer's disease or schizophrenia. Inflammation or even sepsis can be ameliorated by the agonistic acting compounds. Preparations RG3487, SEN34625/WYE-103914, SEN12333, ABT-107, Clozapine, GTS-21, CNI-1493, and AR-R17779 are representative examples of the novel compounds with affinity toward the α7 nAChR. Pharmacological, toxicological, and medicinal significance of α7 nAChR are discussed throughout this paper.
- Klíčová slova
- Alzheimer’s disease, agonist, antagonist, cholinergic anti-inflammatory pathway, cognitive disorder, inflammation, schizophrenia,
- MeSH
- acetylcholin farmakologie MeSH
- agonisté excitačních aminokyselin * farmakologie toxicita MeSH
- alfa7 nikotinové acetylcholinové receptory agonisté antagonisté a inhibitory fyziologie MeSH
- antagonisté excitačních aminokyselin * farmakologie toxicita MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- cílená molekulární terapie * MeSH
- lidé MeSH
- memantin farmakologie terapeutické užití MeSH
- mozek účinky léků metabolismus MeSH
- oximy farmakologie terapeutické užití MeSH
- pyridinové sloučeniny farmakologie terapeutické užití MeSH
- signální transdukce účinky léků MeSH
- zánět metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- acetylcholin MeSH
- agonisté excitačních aminokyselin * MeSH
- alfa7 nikotinové acetylcholinové receptory MeSH
- antagonisté excitačních aminokyselin * MeSH
- antiflogistika MeSH
- asoxime chloride MeSH Prohlížeč
- memantin MeSH
- oximy MeSH
- pyridinové sloučeniny MeSH
Nicotinic acetylcholine receptors (nAChRs) comprise a large and ancient family of allosteric ion channels mediating synaptic transmission. The vast knowledge about nAChRs has become difficult to navigate. NAChRDB is a web-accessible resource of curated residue-level functional annotations of neuromuscular nAChRs. Interactive three-dimensional (3D) visualization and sequence alignment give further context to this rich and growing collection of experimental observations and computational predictions. NAChRDB is freely available at https://crocodile.ncbr.muni.cz/Apps/NAChRDB/, with interactive tutorials and regular updates to the content and web interface. No installation or user registration is required. NAChRDB is accessible through any modern internet browser on desktops and mobile devices. By providing immediate and systematic access to practical knowledge gained through decades of research, NAChRDB represents a powerful educational tool and helps guide discovery by revealing gaps in current knowledge and aiding the interpretation of results of molecular and structural biology experiments or computational studies.
- Publikační typ
- časopisecké články MeSH
The emergence of the novel ß-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in a global pandemic of coronavirus disease 2019 (COVID-19). Clinical studies have documented that potentially severe neurological symptoms are associated with SARS-CoV-2 infection, thereby suggesting direct CNS penetration by the virus. Prior studies have demonstrated that the destructive neurological effects of rabies virus (RABV) infections are mediated by CNS transport of the virus tightly bound to the nicotinic acetylcholine receptor (nAChR). By comparison, it has been hypothesized that a similar mechanism exists to explain the multiple neurological effects of SARS-CoV-2 via binding to peripheral nAChRs followed by orthograde or retrograde transport into the CNS. Genetic engineering of the RABV has been employed to generate novel vaccines consisting of non-replicating RABV particles expressing chimeric capsid proteins containing human immunodeficiency virus 1 (HIV-1), Middle East respiratory syndrome (MERS-CoV), Ebolavirus, and hepatitis C virus (HCV) sequences. Accordingly, we present a critical discussion that integrates lessons learned from prior RABV research and vaccine development into a working model of a SARS-CoV-2 vaccine that selectively targets and neutralizes CNS penetration of a tightly bound viral nAChR complex.
- MeSH
- Betacoronavirus chemie imunologie MeSH
- COVID-19 MeSH
- glykoprotein S, koronavirus chemie genetika imunologie MeSH
- koronavirové infekce imunologie metabolismus prevence a kontrola virologie MeSH
- lidé MeSH
- nikotinové receptory metabolismus MeSH
- pandemie MeSH
- proteinové domény MeSH
- replikace viru * MeSH
- SARS-CoV-2 MeSH
- vakcíny proti COVID-19 MeSH
- virová pneumonie imunologie virologie MeSH
- virové vakcíny chemie imunologie metabolismus MeSH
- virus rabies genetika fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- glykoprotein S, koronavirus MeSH
- nikotinové receptory MeSH
- spike protein, SARS-CoV-2 MeSH Prohlížeč
- vakcíny proti COVID-19 MeSH
- virové vakcíny MeSH
The mode of inhibition of endplate currents by four esters of 1,1-dimethyl-3-oxybutyl phosphonic acid with different lipophilicities and molecule lengths were estimated by mathematical modeling based on previous electrophysiological data supplemented by several experiments with rhythmic stimulation. The aim was to discriminate between their receptor and non-receptor effects. It was shown that all esters have a two-component mechanism of depression: inhibition of the receptor open channel and allosteric modulation of the receptor-channel complex. The ratio of both functional components depends on the length and lipophilicity of the esters. Short and less lipophilic esters mostly act as open channel inhibitors and the rate of inhibition substantially depends on the rate of stimulation, i. e. probability of the receptor-channel opening. As the length of the ester radicals and their lipophilicity increased, these compounds were more active as allosteric receptor inhibitors, probably hindering the function of nAChRs from the lipid annulus.
- MeSH
- alosterická regulace účinky léků MeSH
- cholinergní antagonisté farmakologie MeSH
- kyseliny fosforité farmakologie MeSH
- membránové potenciály účinky léků MeSH
- nervosvalová ploténka účinky léků fyziologie MeSH
- Rana pipiens MeSH
- Ranidae fyziologie MeSH
- receptory cholinergní metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cholinergní antagonisté MeSH
- kyseliny fosforité MeSH
- phosphonic acid MeSH Prohlížeč
- receptory cholinergní MeSH