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Differential effects of calcium channel antagonists on tityustoxin and ouabain-induced release of [3H]acetylcholine from brain cortical slices.

In this paper, the effect of calcium channel blockers on acetylcholine release induced by tityustoxin and ouabain in rat brain cortical slices is described. Cadmium, a non-specific blocker of calcium channels, inhibited the release of ACh induced by tityustoxin. L-type calcium channel blockers (verapamil, nifedipine and diltiazen) had no effect on the release of ACh induced by tityustoxin. The release of ACh was also unaffected by nickel, a T-type calcium channel blocker, and the conotoxins GVIA and MVIIC, blockers of N and Q-type calcium channels. Agatoxin IVA, a specific blocker of the P-typ…

Nine residues influence the binding of alpha-bungarotoxin in alpha-subunit region 185-200 of human muscle acetylcholine receptor.

Identification of residues in the skeletal muscle nicotinic acetylcholine receptor (AChR) that bind snake venom alpha-neurotoxin antagonists of acetylcholine [e.g., alpha-bungarotoxin (alpha-BTx)] provides structural information about the neurotransmitter binding region of the receptor. Using synthetic peptides of the human AChR alpha-subunit region 177-208, we previously localized a pharmacologically specific binding site for alpha-BTx in segment 185-199. To define in more detail the residues that influence the binding of alpha-BTx to this region, we prepared 16 peptide analogues of the alpha…

Body Temperature and Discriminative Stimulus Effects of Nicotine and Menthol Aerosols in Male Rats: Role of α4β2 Nicotinic Acetylcholine Receptors.

Menthol, a prevalent additive in tobacco and electronic cigarette products, has been reported to interact with nicotine at both neuropharmacological and behavioral levels. Although menthol alone is not reinforcing, converging evidence suggests that it may modulate the pharmacological and behavioral effects of nicotine through nicotinic acetylcholine receptor (nAChR) mechanisms. Using an inhalation-based rodent model that mimics human exposure to electronic nicotine delivery systems, we examined how menthol aerosol influences nicotine-induced hypothermia, discriminative stimulus effects, and th…

A critical role for α7 nicotinic acetylcholine receptor signaling in myeloid lineage cells in chronic neuropathic and inflammatory pain responses.

Neuroinflammation influences the development of chronic pain, an increasingly prevalent condition impacting the lives of many worldwide. Given the challenges of managing chronic pain, it is essential to explore new neuroimmune targets for the development of safe and effective analgesics. α7 nicotinic acetylcholine receptors (α7 nAChR) have been explored for their role in pain and inflammation. It was hypothesized that α7 nAChR expression within myeloid cells mediates an anti-inflammatory response that mitigates pain states. Two mouse strains were engineered, with deletion of the α7 gene (Chrna…

Potential role of brain nitric oxide in inhibiting α7 nicotinic acetylcholine receptor-mediated suppression of the micturition reflex in rats.

Brain nitric oxide (NO), produced by NO synthase (NOS), exerts both facilitatory and inhibitory effects on micturition. A functional relationship between NO and nicotinic acetylcholine receptors (nAChRs) has been indicated, and we previously reported that stimulation of brain α7 nAChR suppresses the micturition reflex in rats. In this study, we investigated which brain NOS isozyme is involved in micturition regulation and how NO influences α7 nAChR-mediated suppression. Cystometry was performed in urethane-anesthetized male rats using a bladder catheter. SNAP (NO donor), l-NAME (NOS inhibitor)…

The impact of experimental variables in twitch tension recording on triphasic action of phospholipase A2 neurotoxins at the neuromuscular junction and acetylcholine release.

Electrophysiological investigations have previously demonstrated that snake venom phospholipase A2 (PLA2) neurotoxins such as β-bungarotoxin (BuTx), taipoxin, notexin, crotoxin, and ammodytoxin (Amtx), exert a triphasic effect on the release of acetylcholine (ACh) at the neuromuscular junction (NMJ). The first phase is characterized by a transient decrease in twitch height, which is followed by a facilitatory phase during which twitch height exceeds control levels. The final phase is a reduction of twitch height, ultimately leading to paralysis. The manifestation of this triphasic effect occur…

Модуляция ацетилхолинового уровня при помощи гидрохлорида dopezil смягчает остроту экспериментального аутоиммунного энцефаломиелита (EAE) — животной модели множественного склероза.

Множественный склероз (MS) — хроническая аутоиммунная болезнь, характеризующаяся нейроинфламмацией и обезвоживанием, без какого-либо лечения. Предыдущие исследования показали, что кротоксин, нейротоксин, полученный из яда гремучих змей, эффективно смягчает гиперальгезию и клинические симптомы экспериментального аутоиммунного энцефаломиелита (EAE), в сочетании с силикой SBA-15 (CTX-SBA-15), инертной наноструктурной частицой. Эта комбинация затормозила развитие болезни и уменьшила нейронную воспаление. Опираясь на эти результаты, мы провели всеобъемлющий анализ выражения генов для выявления дифф

Совпадение в аннотации оригинала
Multiple sclerosis (MS), is a chronic autoimmune disease characterized by neuroinflammation and demyelination, with no known cure. Previous … pregulated and 491 downregulated compared to the EAE group. Overrepresentation analysis highlighted acetylcholine receptors pathways as significant targets. For validation, donepezil hydrochloride, an acetylcholinesterase inhibitor, was administered (2 mg/kg/day) initiating 12 days after immunization, with body weight monitored every other day. Donepezil improv …

Synthesis and biological evaluation of novel MB327 analogs as resensitizers for desensitized nicotinic acetylcholine receptors after intoxication with nerve agents.

Poisoning with organophosphorus compounds, which can lead to a cholinergic crisis due to the inhibition of acetylcholinesterase and the subsequent accumulation of acetylcholine (ACh) in the synaptic cleft, is a serious problem for which treatment options are currently insufficient. Our approach to broadening the therapeutic spectrum is to use agents that interact directly with desensitized nicotinic acetylcholine receptors (nAChRs) in order to induce functional recovery after ACh overstimulation. Although MB327, one of the most prominent compounds investigated in this context, has already show…

Aberrant splicing of a nicotinic acetylcholine receptor alpha 6 subunit is associated with spinosad tolerance in the thrips predator Orius laevigatus.

Susceptibility to insecticides is one of the limiting factors preventing wider adoption of natural enemies to control insect pest population … rexpressed detoxification genes. Molecular analysis of the target site for spinosyns, the nicotinic acetylcholine receptor (nAChR), revealed increased expression of truncated transcripts of the nAChR α6 subunit in the spinosad selected strain, a mechanism of resistance which was described previously in insect pest species. Collectively, our results demonstrate …

Comparison of Conformations and Interactions with Nicotinic Acetylcholine Receptors for E. coli-Produced and Synthetic Three-Finger Protein SLURP-1.

SLURP-1 is a three-finger human protein targeting nicotinic acetylcholine receptors (nAChRs). The recombinant forms of SLURP-1 produced in E. coli differ in added fusion fragments and in activity. The closest in sequence to the naturally occurring SLURP-1 is the recombinant rSLURP-1, differing by only one additional N-terminal Met residue. sSLURP-1 can be prepared by peptide synthesis and its amino acid sequence is identical to that of the natural protein. In view of recent NMR analysis of the conformational mobility of rSLURP-1 and cryo-electron microscopy structures of complexes of α-bungaro…

Phosphoproteomic of the acetylcholine pathway enables discovery of the PKC-β-PIX-Rac1-PAK cascade as a stimulatory signal for aversive learning.

Acetylcholine is a neuromodulator critical for learning and memory. The cholinesterase inhibitor donepezil increases brain acetylcholine levels and improves Alzheimer's disease (AD)-associated learning disabilities. Acetylcholine activates striatal/nucleus accumbens dopamine receptor D2-expressing medium spiny neurons (D2R-MSNs), which regulate aversive learning through muscarinic receptor M1 (M1R). However, how acetylcholine stimulates learning beyond M1Rs remains unresolved. Here, we found that acetylcholine stimulated protein kinase C (PKC) in mouse striatal/nucleus accumbens. Our original …

Lyophilization Serves as an Effective Strategy for Drug Development of the α9α10 Nicotinic Acetylcholine Receptor Antagonist α-Conotoxin GeXIVA[1,2].

α-Conotoxin GeXIVA[1,2] is a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype. It has the advantages of strong efficacy, no tolerance, and no effect on motor function, which has been expected help patients with neuropathic pain. However, drug development for clinical use is severely limited owing to its instability. Lyophilization is applied as the most preferred method to solve this problem. The prepared lyophilized powder is characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and Fourier transform i…

Gene expression profiles of the muscarinic acetylcholine receptors in brain regions relating to filial imprinting of newly-hatched domestic chicks.

Muscarinic acetylcholine receptors (mAChRs) in the central nervous system play an important role in regulating complex functions such as learning, memory, and selective attention. Five subtypes of the mAChRs (M1-M5) have been identified in mammals, and are classified into two subfamilies: excitatory (M1, M3, and M5) and inhibitory (M2 and M4) subfamilies. Filial imprinting of domestic chicks is a useful model in the laboratory to investigate the mechanisms of memory formation in early learning. We recently found that mAChRs in the intermediate medial mesopallium (IMM) are involved in the memor…

Two mutations in the nicotinic acetylcholine receptor subunit A4 (CHRNA4) in a family with autosomal dominant sleep-related hypermotor epilepsy.

Sleep-related hypermotor epilepsy, or nocturnal frontal lobe epilepsy, as it was formerly called, is a focal epilepsy with mostly sleep-related seizures of hypermotor, tonic or dystonic semiology. Sleep-related hypermotor epilepsy may be attributed to a monogenetic cause with autosomal dominant inheritance. Mutations are described in different genes, including the genes for three subunits of the nicotinic acetylcholine receptor. We present a family with members over four generations exhibiting sleep-related hypermotor epilepsy. Genetic testing was available for three members from three generat…

Functional validation of nicotinic acetylcholine receptor (nAChR) α6 as a target of spinosyns in Spodoptera exigua utilizing the CRISPR/Cas9 system.

BACKGROUND: The beet armyworm, Spodoptera exigua, is a serious agricultural pest that is primarily controlled using chemical insecticides. Recently, resistance to the insecticide spinosad has been described in S. exigua field populations. To date, there has been no functional evidence proving the involvement of the nicotinic acetylcholine receptor (nAChR) α6 mutation in spinosad resistance in S. exigua. RESULTS: In this study, using the CRISPR/Cas9 genome-editing system, a homozygous strain (Seα6-KO) with approximately 1760-bp deletion within Seα6 in S. exigua causing a premature truncation o…

Unexpected loss of sensitivity to the nicotinic acetylcholine receptor antagonist activity of mecamylamine and dihydro-β-erythroidine in nicotine-tolerant mice.

OBJECTIVES: There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment. METHODS: Schedule-controlled responding and hypothermia were selected for study because they have …

Changes in alpha-7 nicotinic acetylcholine receptor and macrophage polarization state participate in the regulation of cervical remodeling in pregnant rats†.

To test the hypothesis that changes in alpha-7 nicotinic acetylcholine receptor (α7nAChR) expression on macrophages and macrophage polarization participate in cervical remodeling during normal pregnancy, pregnant rats from gestational days (GDs) 14, 16, 18, 20, and 22 were used in the present study. The expression of α7nAChR on macrophages and the numbers of M1 and M2 macrophages were detected by double immunofluorescence staining. The levels of α7nAChR and collagens were detected by western blotting. M1 markers (inducible nitric oxide synthase and inflammatory cytokines) and M2 markers (argin…

Differential effects of spinal motor neuron-derived and skeletal muscle-derived Rspo2 on acetylcholine receptor clustering at the neuromuscular junction.

We recently reported that R-spondin 2 (Rspo2), a secreted activator of Wnt/β-catenin signaling, promotes acetylcholine receptor (AChR) clustering and neuromuscular junction (NMJ) formation via its receptor, Lgr5. Rspo2 is expressed highly in spinal motor neurons (SMNs) and marginally in the skeletal muscle, but the origin of Rspo2 at the NMJ remains elusive. We rescued Rspo2-deficient (Rspo2-/-) mice by specifically expressing Rspo2 in the skeletal muscle and SMNs. SMN-specific Rspo2 mitigated or over-corrected abnormal features of the NMJs and AChR clusters observed in Rspo2-/- mice including…

Sex difference in counts of α4 and α7 nicotinic acetylcholine receptors in the nasal polyps of adults with or without exposure to tobacco smoke.

OBJECTIVE: To assess counts of α4 and α7 nicotinic acetylcholine receptors in nasal polyps of adults with or without long-term exposure to cigarette tobacco smoke. METHODS: Twenty-two patients with and 22 patients without exposure to cigarette tobacco smoke participated in the study. After endoscopic polypectomy, the fragments of the nasal polyps were analysed by immunohistochemistry. RESULTS: Compared to patients with no exposure, patients with exposure showed higher counts of α4 and α7 nicotinic acetylcholine receptors (t-test, p 0.05). CONCLUSION: Exposure to cigarette tobacco smoke may …