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1.
M. V. Skok 《Neurophysiology》2007,39(4-5):264-271
Nicotinic acetylcholine receptors (nAChRs) were initially discovered and studied as mediators of fast synaptic transmission
in neuromuscular junctions and autonomic ganglia. Later on, they were found in the brain and in many nonexcitable tissues
where they regulate vital cellular functions and the activity of other receptors. Primary immune organs, the bone marrow and
thymus, are innervated with cholinergic nerves, which mediate the control of lymphopoiesis provided by the autonomic nervous
system. In addition, lymphocytes are able to produce endogenous acetylcholine that can regulate the immune processes in an
auto/paracrine way. Correspondingly, both T and B lymphocytes express functional nAChRs involved in the regulation of development
and activation of these cells. This review describes the structure and roles of nAChRs in the immune system with regard to
its potential regulation by the autonomic nervous system, as well as by self sources of endogenous agonists.
Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 307–314, July–October, 2007. 相似文献
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Sandall DW Satkunanathan N Keays DA Polidano MA Liping X Pham V Down JG Khalil Z Livett BG Gayler KR 《Biochemistry》2003,42(22):6904-6911
3.
Lester RA 《Bioorganic & medicinal chemistry letters》2004,14(8):1897-1900
Consideration of the activation and desensitization properties of neuronal nicotinic acetylcholine receptors (nAChRs) predicts that there should be a range of concentrations over which low ambient levels of agonist can continuously open nAChR channels. These findings support the idea that postsynaptic nAChRs may participate in unconventional cellular signaling mediated by the release of acetylcholine from diffusely distributed non-synaptic cholinergic varicosities. 相似文献
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Khalil Hajiasgharzadeh Saeed Sadigh-Eteghad Behzad Mansoori Ahad Mokhtarzadeh Dariush Shanehbandi Mohammad Amin Doustvandi Zahra Asadzadeh Behzad Baradaran 《Journal of cellular physiology》2019,234(9):14666-14679
The lung tissue expresses the cholinergic system including nicotinic acetylcholine receptors (nAChRs) which included in many physiologic and pathologic processes. Mounting evidence revealed that these receptors have important roles in lung carcinogenesis via modulating either stimulatory or inhibitory signaling pathways. Among different members of nicotinic receptors family, alpha7-subtype of nAChR (α7nAChR) is a critical mediator involved in both inflammatory responses and cancers. Several studies have shown that this receptor is the most powerful regulator of responses that stimulate lung cancer processes such as proliferation, angiogenesis, metastasis, and inhibition of apoptosis. Moreover, aside from its roles in the regulation of cancer pathways, there is growing evidence indicating that α7nAChR has profound impacts on lung inflammation through the cholinergic anti-inflammatory pathway. Regarding such diverse effects as well as the critical roles of nicotine as an activator of α7nAChR on lung cancer pathogenesis, its modulation has emerged as a promising target for drug developments. In this review, we aim to highlight the detrimental as well as the possible beneficial influences of α7nAChR downstream signaling cascades in the control of lung inflammation and cancer-associated properties. Consequently, by considering the significant global burden of lung cancer, delineating the complex influences of α7 receptors would be of great interest in designing novel anticancer and anti-inflammatory strategies for the patients suffering from lung cancer. 相似文献
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Zhenhua Pan Mengwen Zhao Yonglin Peng 《Journal of biomolecular structure & dynamics》2019,37(11):2938-2948
Nicotinic acetylcholine receptors (nAChRs) are pentamers formed by subunits from a large multigene family and are highly variable in kinetic, electrophysiological and pharmacological properties. Due to the essential roles of nAChRs in many physiological procedures and diversity in function, identifying the function-related sites specific to each subunit is not only necessary to understand the properties of the receptors but also useful to design potential therapeutic compounds that target these macromolecules for treating a series of central neuronal disorders. By conducting a detailed function divergence analysis on nine neuronal nAChR subunits from representative vertebrate species, we revealed the existence of significant functional variation between most subunit pairs. Specifically, 44 unique residues were identified for the α7 subunit, while another 22 residues that were likely responsible for the specific features of other subunits were detected. By mapping these sites onto the 3?D structure of the human α7 subunit, a structure-function relationship profile was revealed. Our results suggested that the functional divergence related sites clustered in the ligand binding domain, the β2–β3 linker close to the N-terminal α-helix, the intracellular linkers between transmembrane domains, and the “transition zone” may have experienced altered evolutionary rates. The former two regions may be potential binding sites for the α7* subtype-specific allosteric modulators, while the latter region is likely to be subtype-specific allosteric modulations of the heteropentameric descendants such as the α4β2* nAChRs.
Communicated by Ramaswamy H. Sarma 相似文献
8.
Calcium modulation and high calcium permeability of neuronal nicotinic acetylcholine receptors. 总被引:36,自引:0,他引:36
Two properties were found to distinguish neuronal from muscle nicotinic acetylcholine receptors (nAChRs). First, neuronal nAChRs have a greater Ca2+ permeability. The high Ca2+ flux through neuronal nAChRs activates a Ca(2+)-dependent Cl- conductance, and the Ca2+ to Cs+ permeability ratio (PCa/PCs) is 7 times greater for neuronal than for muscle nAChRs. A second difference between the receptor types is that neuronal nAChRs are potently modulated by physiological levels of external Ca2+. Neuronal nAChR currents are enhanced by external Ca2+ in a dose-dependent manner. The results indicate that changes in extracellular Ca2+ modulate neuronal nAChRs and may modulate cholinergic synapses in the CNS. Also, activation of neuronal nAChRs produces a significant influx of Ca2+ that could be an important intracellular signal. 相似文献
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Brown LA Jones AK Buckingham SD Mee CJ Sattelle DB 《International journal for parasitology》2006,36(6):617-624
Following the complete sequencing of the genome of the free-living nematode, Caenorhabditis elegans, in 1998, rapid advances have been made in assigning functions to many genes. Forward and reverse genetics have been used to identify novel components of synaptic transmission as well as determine the key components of antiparasitic drug targets. The nicotinic acetylcholine receptors (nAChRs) are prototypical ligand-gated ion channels. The functions of these transmembrane proteins and the roles of the different members of their extensive subunit families are increasingly well characterised. The simple nervous system of C. elegans possesses one of the largest nicotinic acetylcholine receptor gene families known for any organism and a combination of genetic, microarray, physiological and reporter gene expression studies have added greatly to our understanding of the components of nematode muscle and neuronal nAChR subtypes. Chemistry-to-gene screens have identified five subunits that are components of nAChRs sensitive to the antiparasitic drug, levamisole. A novel, validated target acting downstream of the levamisole-sensitive nAChR has also been identified in such screens. Physiology and molecular biology studies on nAChRs of parasitic nematodes have also identified levamisole-sensitive and insensitive subtypes and further subdivisions are under investigation. 相似文献
12.
Cognitive Deficits in Schizophrenia: Focus on Neuronal Nicotinic Acetylcholine Receptors and Smoking
Patients with schizophrenia present with deficits in specific areas of cognition. These are quantifiable by neuropsychological
testing and can be clinically observable as negative signs. Concomitantly, they self-administer nicotine in the form of cigarette
smoking. Nicotine dependence is more prevalent in this patient population when compared to other psychiatric conditions or
to non-mentally ill people. The target for nicotine is the neuronal nicotinic acetylcholine receptor (nAChR). There is ample
evidence that these receptors are involved in normal cognitive operations within the brain. This review describes neuronal
nAChR structure and function, focusing on both cholinergic agonist-induced nAChR desensitization and nAChR up-regulation.
The several mechanisms proposed for the nAChR up-regulation are examined in detail. Desensitization and up-regulation of nAChRs
may be relevant to the physiopathology of schizophrenia. The participation of several subtypes of neuronal nAChRs in the cognitive
processing of non-mentally ill persons and schizophrenic patients is reviewed. The role of smoking is then examined as a possible
cognitive remediator in this psychiatric condition. Finally, pharmacological strategies focused on neuronal nAChRs are discussed
as possible therapeutic avenues that may ameliorate the cognitive deficits of schizophrenia. 相似文献
13.
Nicotinic acetylcholine receptors (nAChRs) are diverse members of the neurotransmitter-gated ion channel superfamily and play critical roles in chemical signaling throughout the nervous system. The present study establishes for the first time the acute functional effects of sertraline (Zoloft), paroxetine (Paxil), nefazodone (Serzone), and venlafaxine (Effexor) on two human and one chick nAChR subtype. This study also confirms previous findings of nAChR functional block by fluoxetine (Prozac). Function of human muscle-type nAChR (alpha1/beta gammadelta) in TE671/RD cells, human autonomic nAChR (alpha3/beta4alpha5 +/- beta2) in SH-SY5Y neuroblastoma cells, or chick V274T mutant alpha7-nAChR heterologously expressed in native nAChR-null SH-EP1 epithelial cells was measured using 86Rb+ efflux assays. Functional blockade of human muscle-type and autonomic nAChRs is produced by each of the drugs in the low to intermediate micromolar range, and functional blockade of chick V274T-alpha7-nAChR is produced in the intermediate to high micromolar range. Functional blockade is insurmountable by increasing agonist concentrations at each nAChR subtype tested for each of these drugs, suggesting noncompetitive inhibition of nAChR function. These studies open the possibilities that nAChR subtypes in the brain could be targets for therapeutic antidepressants and could play roles in clinical depression. 相似文献
14.
Treinin M 《Biotechnology journal》2008,3(12):1539-1547
Nicotinic acetylcholine receptors (nAChRs) belong to a diverse and widely expressed family of ion channels. These receptors are pentamers assembled from multiple combinations of subunits, with different subunit compositions producing receptors having different properties and functions. The diverse functions of nAChRs include an essential role in excitation of skeletal muscles and many modulatory roles throughout the central nervous system. Nicotinic receptors are also implicated in a number of brain pathologies such as epilepsy, schizophrenia, and Alzheimer's disease. Thus, it is important to understand the cellular mechanisms controlling both the numbers and the properties of surface expressed nAChRs. Genetic analysis in Caenorhabditis elegans identified a number of proteins specifically needed for biogenesis of nAChRs. Among these proteins is RIC-3, a member of a family of proteins having conserved structure and function. RIC-3 influences both surface expression and properties of nAChRs and its effects are subtype specific. Here we suggest that receptor-specific chaperones such as RIC-3 may play important roles in controlling receptor diversity by selectively regulating surface expression of nAChRs having specific subunit compositions. 相似文献
15.
Zheng G Zhang Z Pivavarchyk M Deaciuc AG Dwoskin LP Crooks PA 《Bioorganic & medicinal chemistry letters》2007,17(24):6734-6738
A series of conformationally restricted bis-azaaromatic quaternary ammonium salts (3 and 4) have been designed and synthesized in order to investigate the possible binding conformations of N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; 2), a compound which potently inhibits neuronal nicotinic acetylcholine receptors (nAChRs) mediating nicotine-evoked dopamine release. The preliminary structure–activity relationships of these new analogues suggest that bPiDDB binds in an extended conformation at the nAChR binding site, and that flexibility of the linker may be important for its high potency in inhibiting nAChRs mediating nicotine-evoked dopamine release. 相似文献
16.
Barbara GS Grünewald B Paute S Gauthier M Raymond-Delpech V 《Invertebrate neuroscience : IN》2008,8(1):19-29
In insects, acetylcholine (ACh) is the main neurotransmitter, and nicotinic acetylcholine receptors (nAChRs) mediate fast
cholinergic synaptic transmission. In the honeybee, nAChRs are expressed in diverse structures including the primary olfactory
centres of the brain, the antennal lobes (AL) and the mushroom bodies. Whole-cell, voltage-clamp recordings were used to characterize
the nAChRs present on cultured AL cells from adult honeybee, Apis mellifera. In 90% of the cells, applications of ACh induced fast inward currents that desensitized slowly. The classical nicotinic
agonists nicotine and imidacloprid elicited respectively 45 and 43% of the maximum ACh-induced currents. The ACh-elicited
currents were blocked by nicotinic antagonists methyllycaconitine, dihydroxy-β-erythroidine and α-bungarotoxin. The nAChRs
on adult AL cells are cation permeable channels. Our data indicate the existence of functional nAChRs on adult AL cells that
differ from nAChRs on pupal Kenyon cells from mushroom bodies by their pharmacological profile and ionic permeability, suggesting
that these receptors could be implicated in different functions. 相似文献
17.
Insect nicotinic acetylcholine receptors (nAChRs) play a central role in mediating neuronal synaptic transmission and are the target sites for the increasingly important group of neonicotinoid insecticides. Six nicotinic acetylcholine receptor (nAChR) subunits (four alpha-type and two beta-type) have been cloned previously from the model insect species Drosophila melanogaster. Despite extensive efforts, it has not been possible to generate functional recombinant nAChRs by heterologous expression of any combination of these six subunits. It has, however, been possible to express functional hybrid receptors when Drosophila alpha subunits are co-expressed with vertebrate beta subunits. This has led to the assumption that successful heterologous expression might require an, as yet, uncloned beta-type insect subunit. Examination of the recently completed Drosophila genomic sequence data has identified a novel putative nAChR beta-type subunit. Here we report the molecular cloning, heterologous expression and characterization of this putative Drosophila nAChR subunit (Dbeta3). Phylogenetic comparisons with other ligand-gated ion channel subunit sequences support its classification as a nAChR subunit but show it to be a distantly related member of this neurotransmitter receptor subunit family. Evidence that the Dbeta3 subunit is able to coassemble with other Drosophila nAChR subunits and contribute to recombinant nAChRs has been obtained by both radioligand binding and coimmunoprecipitation studies in transfected Drosophila S2 cells. 相似文献
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19.
Nicotinic acetylcholine receptors in cultured neurons from the hippocampus and brain stem of the rat characterized by single channel recording 总被引:3,自引:0,他引:3
Y Aracava S S Deshpande K L Swanson H Rapoport S Wonnacott G Lunt E X Albuquerque 《FEBS letters》1987,222(1):63-70
Single channel recording techniques have been applied to neurons cultured from the hippocampus and the respiratory area of the brain stem of fetal rats in order to search for nicotinic acetylcholine receptors (nAChR) in the central nervous system. In addition to acetylcholine (ACh), the potent and specific agonist (+)-anatoxin-a was also used to characterize nicotinic channels. nAChRs were concentrated on the somal surface near the base of the apical dendrite, and in some patches their density was sufficient to record 2 or more channel openings simultaneously. Although a multiplicity of conductance states was also evident, the predominant population showed a single channel conductance of 20 pS at 10 degrees C. Thus, these neuronal nAChRs resembled the embryonic or denervated-type nAChRs in muscle. However, channel opening and closing kinetics were faster than reported for similar conductance channels in muscle. Therefore the nicotinic channels described here are similar but not identical to those of the well-characterized muscle nAChR, in agreement with biochemical, pharmacological, and molecular genetic studies on brain AChR. 相似文献
20.
Electrophysiology of a chick neuronal nicotinic acetylcholine receptor expressed in Xenopus oocytes after cDNA injection 总被引:12,自引:0,他引:12
Brain nicotinic acetylcholine receptors (nAChRs) are made up of protein subunits that differ from those constituting muscle nAChRs. To characterize the physiological properties of one class of avian brain nicotinic receptor, we injected the nuclei of Xenopus oocytes with full-length cDNAs for the ligand binding (alpha 4) and structural (n alpha) subunits. Injected oocytes had large ACh-induced currents in the microampere range that were insensitive to alpha-bungarotoxin, as expected for neuronal nAChRs. We found that these brain nAChRs incorporate at least two alpha 4 subunits and that their functional properties differ from muscle nAChRs in at least two respects: the elementary conductance is considerably smaller (20 pS), and channels in outside out patches stop functioning within a few minutes. 相似文献