Nicotinic acetylcholine receptors: from structure to brain function

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels and can be divided into two groups: muscle receptors, which are found at the skeletal neuromuscular junction where they mediate neuromuscular transmission, and neuronal receptors, which are found throughout the peripheral and central nervous system where they are involved in fast synaptic transmission. nAChRs are pentameric structures that are made up of combinations of individual subunits. Twelve neuronal nAChR subunits have been described, α2–α10 and β2–β4; these are differentially expressed throughout the nervous system and combine to form nAChRs with a wide range of physiological and pharmacological profiles. The nAChR has been proposed as a model of an allosteric protein in which effects arising from the binding of a ligand to a site on the protein can lead to changes in another part of the molecule. A great deal is known about the structure of the pentameric receptor. The extracellular domain contains binding sites for numerous ligands, which alter receptor behavior through allosteric mechanisms. Functional studies have revealed that nAChRs contribute to the control of resting membrane potential, modulation of synaptic transmission and mediation of fast excitatory transmission. To date, ten genes have been identified in the human genome coding for the nAChRs. nAChRs have been demonstrated to be involved in cognitive processes such as learning and memory and control of movement in normal subjects. Recent data from knockout animals has extended the understanding of nAChR function. Dysfunction of nAChR has been linked to a number of human diseases such as schizophrenia, Alzheimer's and Parkinson's diseases. nAChRs also play a significant role in nicotine addiction, which is a major public health concern. A genetically transmissible epilepsy, ADNFLE, has been associated with specific mutations in the gene coding for the α4 or β2 subunits, which leads to altered receptor properties. Electronic Publication     

The behavioural effects of lorazepam are poorly related to its concentration in the brain

The brain and plasma pharmacokinetics of lorazepam were investigated in rats that had received 5 once daily injections of 0.5 or 1.0 mg/kg of the compound. The sedative effects of the drug were also assessed using a holeboard test. Thirty minutes after the final injection of 1.0 mg/kg lorazepam animals showed a similar degree of sedation to animals tested 90 min after their final injection of 0.5 mg/kg, despite having brain concentrations of lorazepam that were 3 times higher. Four hours after 0.5 mg/kg lorazepam, when the concentration of lorazepam in the brain was very low, animals' head-dipping and locomotor activity scores were still only 60% of the controls' scores. It is concluded that brain concentrations of lorazepam are of little use in predicting the behavioural effects of the compound.     

Involvement of brain trace amines in the behavioural effects of phenelzine

The MAO inhibitor phenelzine (PLZ) at a dose of 25 mg/kg does not affect the behavior of rats. In contrast, the equivalent dose of a deuterated analog (,,,-tetradeutero-PLZ, d₄PLZ) elicits a biphasic behavioral syndrome in rats. In an attempt to correlate changes in cerebral monoamines with behavior, the concentration of various amines were measured at various times after the administration of either d₄PLZ or PLZ (25 mg/kg). In general, PLZ and d₄PLZ caused elevations in brain amine levels, particularly in the time period 2–12 hours after drug administration. Furthermore, d₄PLZ increased the concentrations of serotonin (5-HT), phenylethylamine (PE), tryptamine (T),meta-tyramine (mTA), and 3-methoxytyramine (3-MT) to a greater extent than PLZ. Since the time course of behavioral excitation closely parallels the elevations in T and PE levels in the brain and since the percentage increases in PE and T levels following d₄PLZ compared to PLZ treatment were substantially greater than those of the other amines, it was postulated that PE and T are involved in d₄PLZ-induced behaviors.Abbreviations used (PLZ) Phenelzine - (d₄PLZ) ,,,-tetradeuterophenelzine - (DA) dopamine - (NA) noradrenaline - (5-HT) 5-hydroxytryptamine - (PE) phenylethylamine - (d₄PE) ,,,-tetradeuterophenyl-ethylamine - (pTA) para-tyramine - (mTA) meta-tyramine - (T) tryptamine - (3-MT) 3-methoxytyramine     

三叶肽：从结构到功能

三叶结构域是一段由38－39个氨基酸组成的多肽序列,其中包含6个高度保守的半胱氨酸残基,这6个半胱氨酸残基以1－5,2－4,3－6的交联方式形成三对二硫,窝囊鑫肽链折叠成特征性的三叶结构。已发现的哺乳动物三叶肽有三种：pS1、SP及ITF。三叶肽通常位于消化道腔面的粘膜层,具有保护和修复功能,在维持粘膜的完整性中发挥着重要作用。     

Protein tyrosine phosphatases: from structure to function

In the past few years, a diverse family of receptor-like and nontransmembrane protein tyrosine phosphatases (PTPases) have been identified and characterized at the level of primary structure. Progress is now being made towards defining physiological processes in which the activity of PTPases is important. One thing seems clear: the PTPases cannot be regarded simply as antagonists of the protein tyrosine kinases (PTKs)--rather, they have the potential to act both positively and negatively in mediating cellular signalling responses.     

Pore-forming protein toxins: from structure to function

Pore-forming protein toxins (PFTs) are one of Nature's most potent biological weapons. An essential feature of their toxicity is the remarkable property that PFTs can exist either in a stable water-soluble state or as an integral membrane pore. In order to convert from the water-soluble to the membrane state, the toxin must undergo large conformational changes. There are now more than a dozen PFTs for which crystal structures have been determined and the nature of the conformational changes they must undergo is beginning to be understood. Although they differ markedly in their primary, secondary, tertiary and quaternary structures, nearly all can be classified into one of two families based on the types of pores they are thought to form: alpha-PFTs or beta-PFTs. Recent work suggests a number of common features in the mechanism of membrane insertion may exist for each class.     

Type II secretion: from structure to function

Gram-negative bacteria use the type II secretion system to transport a large number of secreted proteins from the periplasmic space into the extracellular environment. Many of the secreted proteins are major virulence factors in plants and animals. The components of the type II secretion system are located in both the inner and outer membranes where they assemble into a multi-protein, cell-envelope spanning, complex. This review discusses recent progress, particularly newly published structures obtained by X-ray crystallography and electron microscopy that have increased our understanding of how the type II secretion apparatus functions and the role that individual proteins play in this complex system.     

Artificial diiron proteins: from structure to function

De novo protein design provides an attractive approach for the construction of models to probe the features required for the function of complex metalloproteins. These minimal models contain the essential elements believed necessary for activity of the protein. In this article, we summarize the design, structure determination, and functional properties of a family of artificial diiron proteins.     

NMR-spectroscopic analysis of mixtures: from structure to function

NMR spectroscopy as a particularly information-rich method offers unique opportunities for improving the structural and functional characterization of metabolomes, which will be essential for advancing the understanding of many biological processes. Whereas traditionally NMR spectroscopy was mostly relegated to the characterization of pure compounds, the past few years have seen a surge of interest in using NMR-spectroscopic techniques for characterizing complex metabolite mixtures. Development of new methods was motivated partly by the realization that using NMR for the analysis of metabolite mixtures can help identify otherwise inaccessible small molecules, for example compounds that are prone to chemical decomposition and thus cannot be isolated. Furthermore, comparative metabolomics and statistical analyses of NMR spectra have proven highly effective at identifying novel and known metabolites that correlate with changes in genotype or phenotype. In this review, we provide an overview of the range of NMR-spectroscopic techniques recently developed for characterizing metabolite mixtures, including methods used in discovery-oriented natural product chemistry, in the study of metabolite biosynthesis and function, or for comparative analyses of entire metabolomes.     

Brain foods: the effects of nutrients on brain function

It has long been suspected that the relative abundance of specific nutrients can affect cognitive processes and emotions. Newly described influences of dietary factors on neuronal function and synaptic plasticity have revealed some of the vital mechanisms that are responsible for the action of diet on brain health and mental function. Several gut hormones that can enter the brain, or that are produced in the brain itself, influence cognitive ability. In addition, well-established regulators of synaptic plasticity, such as brain-derived neurotrophic factor, can function as metabolic modulators, responding to peripheral signals such as food intake. Understanding the molecular basis of the effects of food on cognition will help us to determine how best to manipulate diet in order to increase the resistance of neurons to insults and promote mental fitness.     

蟋蟀脑的解剖结构与生理机能

蟋蟀脑由前脑、中脑和后脑三部分组成。前脑由1对蕈形体、中央复合体和视叶构成;每个蕈形体由2个冠、柄及与柄相连的α叶和β叶组成,是信息联络整合部位;中央复合体由中央体和脑桥组成,主要参与感觉信息的加工过程;视叶由神经节层、外髓和内髓组成,是视觉系统的中心。中脑由主要组成成分为嗅觉纤维球的嗅叶组成,是嗅觉系统的中心。后脑向后与食道下神经节相连。     

Hyperbolic function of the neuroelectrical effects in the cerebral form of radiation lesions

A theoretical synthesis of electrical parameters of interaction between gamma radiation and excited membranes of nervous and muscular tissues suggests a correlation between power (dose-rate, R) and duration of exposure (T), of the liminal stimulation of a neuron by gamma radiation: R = 6 + 8/T. In studying early transient neurologic disorders (ETND) the threshold charges of ionizing radiation have been defined for various probabilities of occurrence of one of the ETND symptoms.     

Spread of excitation from the ventromedial hypothalamus to the limbic-reticular structure of the brain

The sequence of origination of the evoked potentials in different regions of the septum amygdale and the reticular formation in response to the gradually increasing stimulation of the hypothalamic ventromedial nucleus was studied. As demonstrated, excitation that initially occurs in the hypothalamic ventromedial nuclei embraced first the structures of the septum and rostral reticular formation and then more caudal region of the reticular formation and amygdala.     

Lessons from lesions: the effects of olfactory bulbectomy

Olfactory bulb removal has been used to examine a wide-rangingnumber of topics. The present review outlines the categoriesof studies employing the technique, discusses some problemswith the methodology and with previous interpretations of observedresults, and suggests some potential avenues of investigation.     

Binding of porphyrin to horseradish peroxidase: effects on structure and function

Spectrofluorimetric and spectrophotometric studies were done to understand the binding of hematoporphyrin, a photosensitizer to horseradish peroxidase (EC1.11.1.7). The binding affinity constant (K) decreases as the state of aggregation of the porphyrin increases, while the number of binding sites (approximately 1) remains unchanged. The interaction appears to be mostly hydrophobic, entropy-driven and endothermic process. Hematoporphyrin potentiates horseradish peroxidase-catalyzed H2O2-mediated NADH oxidation, probably by porphyrin-influenced removal of superoxide radicals, which are generated in the system. Conformational change of the protein due to its interaction with porphyrin may be associated with potentiation of the catalytic activity of the enzyme.