Calcium signaling and molecular mechanisms underlying neurodegenerative diseases

Calcium (Ca²⁺) is a ubiquitous second messenger that regulates various activities in eukaryotic cells. Especially important role calcium plays in excitable cells. Neurons require extremely precise spatial-temporal control of calcium-dependent processes because they regulate such vital functions as synaptic plasticity. Recent evidence indicates that neuronal calcium signaling is abnormal in many of neurodegenerative disorders such as Alzheimer’s disease (AD), Huntington’s disease (HD) and Parkinson’s disease (PD). These diseases represent a major medical, social, financial and scientific problem, but despite enormous research efforts, they are still incurable and only symptomatic relief drugs are available. Thus, new approaches and targets are needed. This review highlight neuronal calcium-signaling abnormalities in these diseases, with particular emphasis on the role of neuronal store-operated Ca²⁺ entry (SOCE) pathway and its potential relevance as a therapeutic target for treatment of neurodegeneration.     

Molecular mechanisms underlying specificity of excitotoxic signaling in neurons

The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy and trauma has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Although calcium ions are considered key regulators of excitotoxicity, new evidence suggests that specific second messenger pathways rather than total Ca(2+) load, are responsible for mediating neuronal degeneration. Glutamate receptors are found localized at the synapse within electron dense structures known as the postsynaptic density (PSD). Localization at the PSD is mediated by binding of glutamate receptors to submembrane proteins such as actin and PDZ containing proteins. PDZ domains are conserved motifs that mediate protein-protein interactions and self-association. In addition to glutamate receptors PDZ-containing proteins bind a multitude of intracellular signal molecules including nitric oxide synthase. In this way PDZ proteins provide a mechanism for clustering glutamate receptors at the synapse together with their corresponding signal transduction proteins. PSD organization may thus facilitate the individual neurotoxic signal mechanisms downstream of receptors during glutamate overactivity. Evidence exists showing that inhibiting signals downstream of glutamate receptors, such as nitric oxide and PARP-1 can reduce excitotoxic insult. Furthermore we have shown that uncoupling the interaction between specific glutamate receptors from their PDZ proteins protects neurons against glutamate-mediated excitotoxicity. These findings have significant implications for the treatment of neurodegenerative diseases using therapeutics that specifically target intracellular protein-protein interactions.     

Possible chemical mechanisms underlying the antitumor activity of S-deoxyleinamycin

Though less potent than the parent natural product leinamycin, S-deoxyleinamycin displays activity against human cancer cell lines that is comparable to many clinically used agents. The results reported here suggest that the 1,2-dithiolan-3-one heterocycle found in S-deoxyleinamycin reacts with thiols to generate a persulfide intermediate (RSS(-)) that could deliver biologically active polysulfides, hydrogen sulfide, and reactive oxygen species (O2*-, H(2)O(2), and HO*) to the interior of cells.     

Impedance-based analysis of mu opioid receptor signaling and underlying mechanisms

The mu opioid receptor is a G-protein coupled receptor able to signal through the Gα_i/o class of G-protein and β-arrestin pathways, stimulating down-stream effector pathways. Signaling bias occurs when different receptor agonists lead to different signaling outcomes. Traditionally these have been studied using end-point assays. Real-time cellular analysis platforms allow for the analysis of the holistic effects of receptor activation as an integrated output. While this allows for different ligands to be compared rapidly, the cellular mechanisms underlying the signal are not well described. Using an impedance based system, the impedance responses for two opioid ligands, morphine and DAMGO were examined.The impedance responses for these two agonists, while showing similar features, were distinct from each other. Some of the mechanisms underlying the mu opioid receptor coupled impedance changes were investigated. It was found that the response is a result of discrete cellular processes, including G-protein signaling and protein kinase phosphorylation.     

Using neuronal populations to study the mechanisms underlying spatial and feature attention

Visual attention affects both perception and neuronal responses. Whether the same neuronal mechanisms mediate spatial attention, which improves perception of attended locations, and nonspatial forms of attention has been a subject of considerable debate. Spatial and feature attention have similar effects on individual neurons. Because visual cortex is retinotopically organized, however, spatial attention can comodulate local neuronal populations, whereas feature attention generally requires more selective modulation. We compared the effects of feature and spatial attention on local and spatially separated populations by recording simultaneously from dozens of neurons in both hemispheres of V4. Feature and spatial attention affect the activity of local populations similarly, modulating both firing rates and correlations between pairs of nearby neurons. However, whereas spatial attention appears to act on local populations, feature attention is coordinated across hemispheres. Our results are consistent with a unified attentional mechanism that can modulate the responses of arbitrary subgroups of neurons.     

电压依赖性离子通道门控的分子机制

５０年代Ｈｏｄｇｋｉｎ和Ｈｕｘｌｅｙ双通道模型及其激活与失活学说,正逐步被８０年代以来的分子生物学和电生理学研究所证实。Ｎａ＾＋、Ｋ＾＋离子通道的激活主要决定于高度保守的带正电荷氨基酸残基密集的Ｓ４段,由膜内向膜外方向的拧改锥样旋转。Ｎａ＾＋通道的失活主要与其Ⅲ－Ⅳ功能区之间的胞内连结襻的“铰链盖”样运动有关;Ｋ＾＋通的失活分Ｎ－、Ｃ－、Ｐ－三型,分别发生在Ｎ－、Ｃ－末端和Ｐ区,其Ｎ型失活与Ｎ－末     

The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory, learning and cognition. Flavonoids have been shown to modulate critical neuronal signalling pathways involved in processes of memory, and therefore are likely to affect synaptic plasticity and long-term potentiation mechanisms, widely considered to provide a basis for memory. Animal dietary supplementation studies have further shown that flavonoid-rich foods are able to reverse age-related spatial memory and spatial learning impairments. A more accurate understanding of how a particular spatial memory task works and of which aspects of memory and learning can be assessed in each case, are necessary for a correct interpretation of data relating to diet-cognition experiments. Further understanding of how specific behavioural tasks relate to the functioning of hippocampal circuitry during learning processes might be also elucidative of the specific observed memory improvements. The overall goal of this review is to give an overview of how the hippocampal circuitry operates as a memory system during behavioural tasks, which we believe will provide a new insight into the underlying mechanisms of the action of flavonoids on cognition.     

Evolved mechanisms underlying wayfinding: further studies on the hunter-gatherer theory of spatial sex differences

Based on Silverman and Eals' hunter-gatherer theory of the origin of sex-specific spatial attributes, the present research sought to identify the evolved mechanisms involved in hunting that contribute to the dimorphism. The focus of these studies was the relationship between three-dimensional mental rotations, the spatial test showing the largest and most reliable sex difference favoring males, and wayfinding in the woods. Space constancy was presumed to be the evolved mechanism fundamental to both of these abilities. Measures of wayfinding were derived by leading subjects individually on a circuitous route through a wooded area, during which they were stopped at prescribed places and required to set an arrow pointing in the direction the walk began. As well, subjects were eventually required to lead the experimenters back to the starting point by the most direct route. In support of the hypotheses, males excelled on the various measures of wayfinding, and wayfinding was significantly related across sexes to mental rotations scores but not to nonrotational spatial abilities or general intelligence.     

The molecular basis of mechanisms underlying polarization vision

The underlying mechanisms of polarization sensitivity (PS) have long remained elusive. For rhabdomeric photoreceptors, questions remain over the high levels of PS measured experimentally. In ciliary photoreceptors, and specifically cones, little direct evidence supports any type of mechanism. In order to promote a greater interest in these fundamental aspects of polarization vision, we examined a varied collection of studies linking membrane biochemistry, protein-protein interactions, molecular ordering and membrane phase behaviour. While initially these studies may seem unrelated to polarization vision, a common narrative emerges. A surprising amount of evidence exists demonstrating the importance of protein-protein interactions in both rhabdomeric and ciliary photoreceptors, indicating the possible long-range ordering of the opsin protein for increased PS. Moreover, we extend this direction by considering how such protein paracrystalline organization arises in all cell types from controlled membrane phase behaviour and propose a universal pathway for PS to occur in both rhabdomeric and cone photoreceptors.     

The underlying mechanisms of type II protein secretion

The cell envelope of Gram-negative bacteria is composed of two membranes, which are separated by the peptidoglycan-containing periplasm. Whereas the envelope forms an essential barrier against harmful substances, it is nevertheless a compartment of intense traffic for large proteins such as enzymes and toxins. Numerous studies dealing with the molecular mechanism of protein secretion have revealed that Gram-negative bacteria evolved different strategies to achieve this process. Among them, the type II secretion mechanism is part of a two-step process. Exoproteins following this pathway are synthesized as signal peptide-containing precursors. After cleavage of the signal peptide, the mature exoproteins are released into the periplasm, where they fold. The type II machinery, also known as the secreton, is responsible for the translocation of the periplasmic intermediates across the OM. The type II system is broadly conserved in Gram-negative bacteria and involves a set of 12-16 different proteins named GspC-M, GspAB, GspN, GspO, and GspS. The type II secretion system is highly reminiscent of the type IV piliation assembly system. Based on findings about the subcellular localisation of the Gsp components, protein-protein interactions between Gsps and their multimerisation status, structural data and electron microscopy observation, it could be proposed a working model that strikingly runs both systems in parallel.     

The interdependence of mechanisms underlying climate-driven vegetation mortality

Climate-driven vegetation mortality is occurring globally and is predicted to increase in the near future. The expected climate feedbacks of regional-scale mortality events have intensified the need to improve the simple mortality algorithms used for future predictions, but uncertainty regarding mortality processes precludes mechanistic modeling. By integrating new evidence from a wide range of fields, we conclude that hydraulic function and carbohydrate and defense metabolism have numerous potential failure points, and that these processes are strongly interdependent, both with each other and with destructive pathogen and insect populations. Crucially, most of these mechanisms and their interdependencies are likely to become amplified under a warmer, drier climate. Here, we outline the observations and experiments needed to test this interdependence and to improve simulations of this emergent global phenomenon.     

Neural mechanisms underlying the evolvability of behaviour

The complexity of nervous systems alters the evolvability of behaviour. Complex nervous systems are phylogenetically constrained; nevertheless particular species-specific behaviours have repeatedly evolved, suggesting a predisposition towards those behaviours. Independently evolved behaviours in animals that share a common neural architecture are generally produced by homologous neural structures, homologous neural pathways and even in the case of some invertebrates, homologous identified neurons. Such parallel evolution has been documented in the chromatic sensitivity of visual systems, motor behaviours and complex social behaviours such as pair-bonding. The appearance of homoplasious behaviours produced by homologous neural substrates suggests that there might be features of these nervous systems that favoured the repeated evolution of particular behaviours. Neuromodulation may be one such feature because it allows anatomically defined neural circuitry to be re-purposed. The developmental, genetic and physiological mechanisms that contribute to nervous system complexity may also bias the evolution of behaviour, thereby affecting the evolvability of species-specific behaviour.     

From spreading depression to spatial cognition

The Laboratory of Neurophysiology of Memory started its existence in 1954 by systematic research into spreading depression of EEG activity of laboratory rodents and by the use of this remarkable phenomenon as a functional ablation method in behavioral research. Its main contributions were in the study of memory formation and consolidation, interhemispheric transfer, motor learning, conditioned taste aversion and spatial orientation and navigation. In the last five years it concentrated on navigation of rats in multiple reference frames, on electrophysiological evidence for the role of hippocampal place cells support of behavior in such dissociated frames, on the analysis of idiothetic and allothetic forms of navigation and on the mathematical methods allowing assessment of the contribution of goal directed locomotion to place cell activity. The methods used in spatial memory research in rats were used for examination of human subjects in a laboratory equipped with a tracking system for humans in the hospital Homolka. Animal models of Alzheimer disease were studied in transgenic mice with the human gene for the beta amyloid precursor protein.