Macroautophagy is a major degradation mechanism of cell components via the lysosome. Macroautophagy greatly contributes to not only cell homeostasis but also the prevention of various diseases. Because macroautophagy proceeds through multi‐step reactions, researchers often face a persistent question of how macroautophagic activity can be measured correctly. To make a straightforward determination of macroautophagic activity, diverse monitoring assays have been developed. Direct measurement of lysosome‐dependent degradation of radioisotopically labeled cell proteins has long been applied. Meanwhile, indirect monitoring procedures have been (...) developed. In these assays, autophagosome marker proteins, microtubule‐associated proteins 1A/1B light chain 3B‐II (LC3B‐II) and gamma‐aminobutyric acid receptor‐associated protein‐II (GABARAP‐II) have been analyzed and the validity of the assays strongly depends on appropriate assessment of the fluctuation of LC3‐II and/or GABARAP‐II levels in the presence or absence of lysosomal inhibitors. This article describes these monitoring methods, paying special attention to the principles and characteristics of each procedure. (shrink)

Computerized relaxation training has been suggested as an effective and easily accessible intervention for individuals with psychological distress. To better elucidate the neural mechanism that underpins the effects of relaxation training, we investigated whether a 10-session computerized relaxation training program changed prefrontal gamma-aminobutyric acid levels and cerebral blood flow in women with psychological distress. We specifically focused on women since they were reported to be more vulnerable to develop stress-related disorders than men. Nineteen women with psychological distress (...) but without a diagnosis of psychiatric disorders received the 10-day computerized relaxation training program that consisted of 30-min cognitive-relaxation training and 10-min breathing-relaxation training per day. At baseline and post-intervention, perceived stress levels, anxiety, fatigue, and sleep quality were assessed by self-report questionnaires. Brain magnetic resonance spectroscopy and arterial spin labeling scans were also performed before and after the intervention to evaluate GABA levels and relative CBF in the prefrontal region. Levels of perceived stress, anxiety, fatigue, and sleep quality improved following 10 sessions of computerized relaxation training, resulting in a significant relief in composite scores of stress-related symptoms. The prefrontal GABA levels decreased, while relative CBF increased after the intervention. In addition, a greater increase in relative prefrontal CBF was associated with better composite scores of stress-related symptoms following the intervention. The current findings suggest that computerized relaxation training may improve stress-related symptoms through modulating the prefrontal GABA levels and CBF in women with psychological distress. (shrink)

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the [gamma]-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn (...) of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue. (shrink)

The neurotransmitters GABA and glutamate have been suggested to play a role in Major Depressive Disorder (MDD) through an imbalance between cortical inhibition and excitation. This effect has been highlighted in higher brain areas, such as the prefrontal cortex, but has also been posited in basic sensory cortices. Based on this, magnetic resonance spectroscopy (MRS) was used to investigate potential changes to GABA+ and glutamate+glutamine (Glx) concentrations within the occipital cortex in MDD patients (n = 25) and healthy controls (n (...) = 25). No difference in occipital GABA+ or Glx concentrations, nor in the GABA+/Glx ratio, was found between groups. An analysis of an extended MDD patient and unmatched control dataset (n = 90) found no correlation between metabolite concentrations and depressive symptoms. These results were integrated with prior studies through metabolite-specific meta-analyses, revealing no difference in occipital GABA and Glx concentrations between patients and controls. An effect of publication year on GABA group differences was found, suggesting that previously reported results may have been artifacts of measurement accuracy. Taken together, our results suggest that, contrary to some prior reports, MRS measurements of occipital GABA and Glx do not differ between MDD patients and controls. (shrink)

Retinoids play an important role in development and differentiation(1,2). Their effect is mediated through nuclear receptors, RAR (α, β and γ) and RXR (α, β and γ),Abbreviations. RAR: retinoic acid receptor; RXR: retinoid X receptor; T3:thyroid hormone receptor; VD3R: vitamin D3 receptor; PPAR: peroxisome proliferator activated receptor; EcR ecdycsone receptor; USP, ultraspiracle; NGFI‐B: also referred to as nur77a; ELP: embryonal long terminal repeat‐binding protein; FTZ‐F1: positive regulator of the fushi tarazu gene in (...) blastodermstage embryos of Drosophila melanogaster; GR: glucocorticoid receptor; ER: estrogen receptor; RARE, retinoic acid response element; PR: progesterone receptor; DR+x: direct repeat with a spacing of x nucleotides; DBD: DNA‐binding domain; CRABP I and II: cellular retinoic acid binding protein type I and II, respectively; MoMLV: Moloney Murine Leukemia Virus; TBP: TATA‐binding protein; TAF: TBP associated factor. which are members of a distinct subclass (hereafter referred to as type II) of the nuclear receptor superfamily that includes the thyroid hormone receptor (T3R), the vitamin D3 receptor (VD3R) and the peroxisome proliferator activated receptor (PPAR). Type II receptors transactivate through binding sites composed of closely related half‐sites (consensus sequence AGG/T TCA) arranged as direct repeats and, with the possible exception of RXR, do not bind to their cognate binding sites as homodimers but require RXR for high affinity binding. RXR thus provides a link between biologically distinct ligand induced pathways and is a potential target for cross‐regulation. In addition, RAR can utilize alternative routes to enhance transcription initiation mediated through transcriptional co‐activators which are expressed in a cell‐type specific manner. (shrink)

In amblyopia, abnormal visual experience during development leads to an enduring loss of visual acuity in adulthood. Physiological studies in animal models suggest that intracortical GABAergic inhibition may mediate visual deficits in amblyopia. To better understand the relationship between visual cortical γ-aminobutyric acid (GABA) and perceptual suppression in persons with amblyopia (PWA), we employed magnetic resonance spectroscopy (MRS) to quantify GABA levels in both PWA and normally-sighted persons (NSP). In the same individuals, we obtained psychophysical measures of perceptual (...) suppression for a variety of ocular configurations. In PWA, we found a robust negative correlation between the depth of amblyopia (the difference in visual acuity between the amblyopic and non-amblyopic eyes) and GABA concentration that was specific to visual cortex and was not observed in a sensorimotor cortical control region. Moreover, lower levels of visual cortical GABA were associated with weaker perceptual suppression of the fellow eye by the amblyopic eye and stronger suppression of the amblyopic eye by the fellow eye. Taken together, our findings provide evidence that intracortical GABAergic inhibition is an important component of the pathology of human amblyopia and suggest possible therapeutic interventions to restore vision in the amblyopic eye through enhancement of visual cortical GABAergic signaling in PWA. (shrink)

Stiff Person Syndrome is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase, the key enzyme in γ -aminobutyric acid synthesis. In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [ 11 C]flumazenil positron emission tomography in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, (...) we found a global reduction of cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS. (shrink)

Alpha‐fetoprotein (AFP)AFP, alpha‐fetoprotein; T3R, thyroid hormone (triiodothyronine) receptor; RAR, retionic acid receptor; erbA, putative thyroid hormone receptor proto‐oncogene products; VDR, vitamin D receptor; MR, mineralocorticoid receptor; GR, glucocorticoid receptor; PR, progesterone receptor; AR, androgen receptor; HRE, hormone response element on DNA; RXR, retionic‐X‐receptor; RAP, receptor auxiliary (accessory) proteins; E, estrogen. is a tumor‐associated fetal marker, associated both with tumor growth and with birth defects. AFP, whose precise function (...) is unknown, has been classified as belonging to a protein superfamily together with albumin and vitamin D‐binding (Gc) protein. AFP has been shown to bind various ligands in vitro including fatty acids, estrogens, thyroid hormones and retinoic acids. The steroid/thyroid nuclear receptor superfamily of proteins has recently become a major focus of biomedical investigation regarding regulation of gene expression. These receptors are thought to bind to DNA‐hormone response elements (HRE) that affect growth, development, differentiation, reproduction and homeostasis. The HREs are known to share DNA sequences with the various members of the nuclear receptor superfamily. In the present report, the possibility of a leucine‐zipper dimerization (heptad) motif in the carboxy‐terminal third domain of both rodent and human AFP is postulated. The presence of nine such hydrophobic repeats in the third domain of the AFP molecule mimics the heptad dimerization repeats found in the retinoic acid, thyroid, e‐erbA and other members of the nuclear receptor superfamily. Computer analysis revealed that the most conservative matching occurred between AFP and the retinoic acid class of receptors. However, other superfamily members displayed 40–60% homology with 5 of 9 AFP heptads. These findings could provide a possible mechanism for explaining the growth‐regulatory properties (both inhibition and enhancement) that have been ascribed to AFP in the last decade. (shrink)

Backgrounds: Transcranial direct current stimulation is a non-invasive brain stimulation technique for the treatment of several psychiatric disorders, e.g., mood disorders and schizophrenia. Therapeutic effects of tDCS are suggested to be produced by bi-directional changes in cortical activities, i.e., increased/decreased cortical excitability via anodal/cathodal stimulation. Although tDCS provides a promising approach for the treatment of psychiatric disorders, its neurobiological mechanisms remain to be explored.Objectives: To review recent findings from neurophysiological, chemical, and brain-network studies, and consider how tDCS ameliorates psychiatric conditions.Findings: (...) Enhancement of excitatory synaptic transmissions through anodal tDCS stimulation is likely to facilitate glutamate transmission and suppress gamma-aminobutyric acid transmission in the cortex. On the other hand, it positively or negatively modulates the activities of dopamine, serotonin, and acetylcholine transmissions in the central nervous system. These neural events by tDCS may change the balance between excitatory and inhibitory inputs. Specifically, multi-session tDCS is thought to promote/regulate information processing efficiency in the cerebral cortical circuit, which induces long-term potentiation by synthesizing various proteins.Conclusions: This review will help understand putative mechanisms underlying the clinical benefits of tDCS from the perspective of neurotransmitters, network dynamics, intracellular events, and related modalities of the brain function. (shrink)

Fatty acids (FAs) are well known to serve as substrates for reactions that provide cells with membranes and energy. In contrast to these metabolic reactions, the physiological importance of FAs themselves known as free FAs (FFAs) in cells remains obscure. Since accumulation of FFAs in cells is toxic, cells must develop mechanisms to detoxify FFAs. One such mechanism is to sequester free polyunsaturated FAs (PUFAs) into a droplet‐like structure assembled by Fas‐Associated Factor 1 (FAF1), a cytosolic protein. This (...) sequestration limits access of PUFAs to Fe2+, thereby preventing Fe2+‐catalyzed PUFA peroxidation. Consequently, assembly of the FAF1‐FFA complex is critical to protect cells from ferroptosis, a cell death pathway triggered by PUFA peroxidation. The observations that free PUFAs in cytosol are not randomly diffused but rather sequestered into a membraneless complex should open new directions to explore signaling pathways by which FFAs regulate cellular physiology. (shrink)

Recent findings necessitate revision of the traditional view of G protein‐coupled receptor (GPCR) signaling and expand the diversity of mechanisms by which receptor signaling influences cell behavior in general. GPCRs elicit signals at the plasma membrane and are then rapidly removed from the cell surface by endocytosis. Internalization of GPCRs has long been thought to serve as a mechanism to terminate the production of second messengers such as cAMP. However, recent studies show that internalized GPCRs can continue (...) to either stimulate or inhibit cAMP production in a sustained manner. They do so by remaining associated with their cognate G protein subunit and adenylyl cyclase at endosomal compartments. Once internalized, the GPCRs produce cellular responses distinct from those elicited at the cell surface. (shrink)

As targeted proteins that move within the cell, the steroid receptors have become very useful probes for understanding the linked phenomena of protein folding and transport. From the study of steroid receptor‐associated proteins it has become clear over the past two years that these receptors are bound to a multiprotein complex containing at least two heat shock proteins, hsp90 and hsp56. Attachment of receptors to this complex in a cell‐free system appears to require the protein unfolding/folding (...) activity of a third heat shock protein, hsp70. Like the oncogenic tyrosine kinase pp60src, steroid receptors bind to this complex of chaperone proteins at the time of their translation. Binding of the receptor to the hsp90 component of the system occurs through the hormone binding domain and is under strict hormonal control. The hormone binding domain of the receptor acts as a transferable regulatory unit that confers both tight hormonal control and hsp90 binding onto chimaeric proteins. The model of folding and transport being developed for steroid receptors leads to some general suggestions regarding the folding and transport of targeted proteins in the cell. (shrink)

Receptor oligomerization plays a key role in maintaining genome stability and restricting protein mutagenesis. When properly folded, protein monomers assemble as oligomeric receptors and interact with environmental ligands. In a gene-centered view, the ligand specificity expressed by these receptors is assumed to be causally predetermined by the cell genome. However, this mechanism does not fully explain how differentiated cells have come to express specific receptor repertoires and which combinatorial codes have been explored to activate their (...) class='Hi'>associated signaling pathways. It is our contention that the plasma membrane acts as the locus where several contextual cues may be integrated. As such it allows the semiotic selection of those receptor configurations that provide cells with the minimum essential requirements for agency. The occurrence of protein misfolding makes it impossible for receptor monomers to assemble along the membrane and to sustain meaningful relationships with environmental ligands. How could a cell lineage deal with these loss-of-function mutations during evolution and restrain gene redundancy accordingly? In this paper, we will be arguing that the easiest way for bacteria clones to accomplish this goal is by getting rid of cells expressing mutated receptor proteins. The mechanism sustaining this cell selection is also occurring in many somatic tissues and its function is currently believed to counteract in vivo protein mutagenesis. Our discussion will be mainly focused on the significance and semiotic nature of the interplay between membrane receptors and the epigenetic control of gene expression, as mediated by the control of mismatched repairing and protein folding mechanisms. (shrink)

Here we review concepts related to an ensemble description of G-protein-coupled receptors. The ensemble is characterized by both inactive and active states, whose equilibrium populations and exchange rates depend sensitively on ligand, environment, and allosteric factors. This review focuses on the adenosine A2 receptor, a prototypical class A GPCR. 19F Nuclear Magnetic Resonance studies show that apo A2AR is characterized by a broad ensemble of conformers, spanning inactive to active states, and resembling states defined earlier for rhodopsin. In (...) keeping with ideas associated with a conformational selection mechanism, addition of agonist serves to allosterically restrict the overall degrees of freedom at the G protein binding interface and bias both states and functional dynamics to facilitate G protein binding and subsequent activation. While the ligand does not necessarily “induce” activation, it does bias sampling of states, increase the cooperativity of the activation process and thus, the lifetimes of functional activation intermediates, while restricting conformational dynamics to that needed for activation. GPCRs represent a ubiquitous class of transmembrane receptors, responsible for cell signaling and cell homeostasis. Their activation gives rise to conformational changes that allow the receptor to engage downstream partners. Activation can be thought of in terms of a free energy landscape associated with distinct conformers, responsible for the process. Here, the action of ligands is seen to alter this landscape by enabling transitions between key intermediates. (shrink)

The mechanisms by which most receptor protein‐tyrosine kinases (RTKs) transmit signals are now well established. Binding of ligand results in the dimerization of receptor monomers followed by transphosphorylation of tyrosine residues within the cytoplasmic domains of the receptors. This tidy picture has, however, some strange characters lurking around the edges. Cases have now been identified in which RTKs lack kinase activity, but, despite being “dead” appear to have roles in signal transduction. Even stranger are the cases in (...) which genes encoding RTKs produce protein products consisting of only a portion of the kinase domain. At least one such “fractured” RTK appears to be involved in signal transduction. Here we describe how these strange molecules might function and discuss the questions associated with their evolution. BioEssays 23:69–76, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

It was initially believed that G‐protein‐coupled receptors, such as metabotropic glutamate receptors, could simply be described as individual proteins that are associated with intracellular signal cascades via G‐proteins. This view is no longer tenable. Today we know that metabotropic glutamate receptors (mGluRs) can dimerize and bind to a variety of proteins in addition to trimeric G‐proteins. These newly identified protein interactions led to the discovery of new regulatory mechanisms that are independent of and sometimes synergistic with the (...) classical G‐protein‐coupled second messenger pathways. Notably, several of these mechanisms connect mGluR‐mediated signaling to other receptor classes, thereby creating a network of different receptor types and associated signal cascades. The intracellular C‐termini of mGluRs play a key role in the regulation of these networks, and various new protein interactions of these domains were described recently. Because mGluRs are involved in a variety of physiological and pathophysiological processes, some of the proteins interacting with this receptor class have potential as valuable pharmaceutical targets. This review will give a comprehensive overview of proteins interacting with mGluR C‐termini, highlight new evolving regulatory mechanisms for glutamatergic signal transduction and discuss possibilities for future drug development. BioEssays 29: 60–73, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

Many biologically active compounds including neurotransmitters, metabolic precursors, and certain drugs are accumulated intracellularly by transporters that are coupled to the transmembrane Na+ gradient. Amino acid neurotransmitter transporters play a key role in the regulation of extracellular amino acid concentrations and termination of neurotransmission in the CNSAbbreviations: CNS, central nervous system; GABA, γ‐aminobutyric acid; cDNA, complementary deoxyribonucleic acid; mRNA, messenger ribonucleic acid; NMDA, N‐methyl‐D‐aspartate; PKC, protein kinase C; PMA, phorbol 12‐myristate 13‐acetate; DAG, diacyl (...) glycerol; R59022, DAG kinase inhibitor; AA, arachidonic acid; ACHC, cis‐3‐aminocyclohexanecarboxylic acid; GAT‐A, ACHC‐sensitive GABA transporter; GAT‐B, β‐alanine‐sensitive GABA transporter; GLY‐1 and GLYT‐1, glycine transporters; PROT‐1, proline transporter; BGT‐1, betaine transporter.. Transporters for the major amino acid neurotransmitters glutamate, GABA, and glycine are found in both neurons and glial cells. Recent work has resulted in the identification of cDNAs encoding several amino acid neurotransmitter transport proteins, all of which belong to the Na+‐and Cl−‐dependent transporter gene family. The diversity of this family suggests a degree of transporter heterogeneity that is greater than that indicated by biochemical and pharmacological studies. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in (...) spite of the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

Retinoic acid (RA), a derivative of vitamin A, is essential for normal mammalian development. Developmental abnormalities induced by RA excess and vitamin A deficiency are different even though they affect the same organ systems, and it is clear that there are intraembryonic tissue differences in the requirement for RA. The developmental functions of RA are mediated by its effects on gene expression. In the nucleus, two different forms of RA bind to and activate two families of nuclear receptors, which (...) themselves co‐operate in initiating the transcription of target genes. In this article I propose that the amount of RA reaching the nucleus in different embryonic tissues is modulated by a mechanism involving three cytoplasmic binding proteins for retinol (CRBP I) and retinoic acid (CRABP I and II). Abnormalities of craniofacial development resulting from exposure of early neural plate stage embryos to RA excess have been studied in some detail; their initial stages involve alteration of both morphological development and the segment‐specific pattern of gene expression in the early hindbrain and its derived neural crest. This system is ideal for studying the relationships between retinoic acid receptors, retinoid binding proteins, and the development of genetic and morphological pattern. (shrink)

Autoantibodies to three eukaryotic 60S ribosomal phosphoproteins P0, P1 and P2 have been found in the sera of 10–20% of patients with systemic lupus erythematosus (SLE). These three proteins share a common epitope contained within the carboxy terminal 22 amino acids of each protein. Because central nervous system disturbances, with major behavioural disorders, occur in a significant fraction of SLE patients, the antiribosomal autoantibodies were measured in this subset of SLE individuals to determine whether or not there was an (...) association. This antibody is present in 90% of SLE patients who were diagnosed as having psychosis, secondary to the disease. (shrink)

We consider the evidence that RA†, the vitamin A metabolite, is involved in three fundamental aspects of the development of the CNS: (1) the stimulation of axon outgrowth in particular neuronal sub‐types; (2) the migration of the neural crest; and (3) the specification of rostrocaudal position in the developing CNS (forebrain, midbrain, hindbrain, spinal cord). The evidence we discuss involves RA‐induction of neurites in cell cultures and explants of neural tissue; the teratological effects of RA on the embryo's nervous system; (...) the observation that RA can be detected endogenously in the spinal cord; and the fact that the receptors and binding proteins for RA are expressed in precise domains and neuronal cell types within the nervous system. (shrink)

Parvalbumins (PVs) are acidic, intracellular Ca2+‐binding proteins of low molecular weight. They are associated with several Ca2+‐mediated cellular activities and physiological processes. It has been suggested that PV might function as a “Ca2+ shuttle” transporting Ca2+ from troponin‐C (TnC) to the sarcoplasmic reticulum (SR) Ca2+ pump during muscle relaxation. Thus, PV may contribute to the performance of rapid, phasic movements by accelerating the contraction–relaxation cycle of fast‐twitch muscle fibers. Interestingly, PVs promote the generation of power stroke in fish by (...) speeding up the rate of relaxation and thus provide impetus to attain maximal sustainable speeds. However, immunological monitoring of diverse tissues demonstrated that PVs are also present in non‐muscle cells. The axoplasmic transport and various intracellular secretory mechanisms including the endocrine secretions seem to be controlled by the Ca2+ regulation machinery. Any defect in the Ca2+ handling apparatus may cause several clinical problems; for instance, PV deficiency alters the neuronal activity, a key mechanism leading to epileptic seizures. Moreover, atypical relaxation of the heart results in diastolic dysfunction, which is a major cause of heart failure predominantly among the aged people. PV may offer a unique potential to correct defective relaxation in energetically compromised failing hearts through PV gene transfer. Consequently, PV gene transfer may present a new therapeutic approach to correct cellular disturbances in Ca2+ signaling pathways of diseased organs. Hence, PVs appear to be amazingly useful candidate proteins regulating a variety of cellular functions through action on Ca2+ flux management. (shrink)

Multidrug-resistant Acinetobacter baumannii is recognized to be among the most difficult antimicrobial-resistant gram negative bacilli to control and treat. One of the major challenges that the pathogenic bacteria face in their host is the scarcity of freely available iron. To survive under such conditions, bacteria express new proteins on their outer membrane and also secrete iron chelators called siderophores. Antibodies directed against these proteins associated with iron uptake exert a bacteriostatic or bactericidal effect against A. baumanii in vitro, by (...) blocking siderophore mediated iron uptake pathways. Attempts should be made to discover peptides that could mimic protein epitopes and possess the same immunogenicity as the whole protein. Subsequently, theoretical methods for epitope prediction have been developed leading to synthesis of such peptides that are important for development of immunodiagnostic tests and vaccines. The present study was designed to in silico resolving the major obstacles in the control or in prevention of the diseases caused by A. baumannii. We exploited bioinformatic tools to better understand and characterize the Baumannii acinetobactin utilization structure of A. baumannii and select appropriate regions as effective B cell epitopes. In conclusion, amino acids 26–191 of cork domain and 321–635 of part of the barrel domain including L4–L9, were selected as vaccine candidates. These two regions contain functional exposed amino acids with higher score of B cell epitopes properties. Majority of amino acids are hydrophilic, flexible, accessible, and favorable for B cells from secondary structure point of view. (shrink)

Homologies in amino‐acid sequence indicate that all known protein kinases share a conserved catalytic core, and, thus, belong to a related family of proteins that have evolved in part from a common ancestoral origin. This family includes cellular kinases, oncogenic viral kinases and their protooncogene counterparts, and growth factor receptors. One of the simplest and certainly the best characterized of the protein kinases at the biochemical level is the kinase that is activated in response to cAMP. The (...) properties of this cAMP‐dependent protein kinase are reviewed with particular emphasis on the features of nucleotide binding and catalytic mechanism that are likely to be shared by all protein kinases. In spite of this conserved catalytic core, these kinases vary widely in overall structure and in the mechanisms by which each is regulated, and these differences also are compared. (shrink)

Recently published work showed that members of the PAQR protein family are activated by cell membrane rigidity and contribute to our ability to eat a wide variety of diets. Cell membranes are primarily composed of phospholipids containing dietarily obtained fatty acids, which poses a challenge to membrane properties because diets can vary greatly in their fatty acid composition and could impart opposite properties to the cellular membranes. In particular, saturated fatty acids (SFAs) can pack tightly and form rigid (...) membranes (like butter at room temperature) while unsaturated fatty acids (UFAs) form more fluid membranes (like vegetable oils). Proteins of the PAQR protein family, characterized by the presence of seven transmembrane domains and a cytosolic N‐terminus, contribute to membrane homeostasis in bacteria, yeasts, and animals. These proteins respond to membrane rigidity by stimulating fatty acid desaturation and incorporation of UFAs into phospholipids and explain the ability of animals to thrive on diets with widely varied fat composition. Also see the video abstract here: https://youtu.be/6ckcvaDdbQg. (shrink)

Since their discovery over two decades ago, the molecular and cellular functions of the NIPSNAP family of proteins (NIPSNAPs) have remained elusive until recently. NIPSNAPs interact with a variety of mitochondrial and cytoplasmic proteins. They have been implicated in multiple cellular processes and associated with different physiologic and pathologic conditions, including pain transmission, Parkinson's disease, and cancer. Recent evidence demonstrated a direct role for NIPSNAP1 and NIPSNAP2 proteins in regulation of mitophagy, a process that is critical for cellular health (...) and maintenance. Importantly, NIPSNAPs contain a 110 amino acid domain that is evolutionary conserved from mammals to bacteria. However, the molecular function of the conserved NIPSNAP domain and its potential role in mitophagy have not been explored. It stands to reason that the highly conserved NIPSNAP domain interacts with a substrate that is ubiquitously present across all species and can perhaps act as a sensor for mitochondrial health. (shrink)

Small gaseous molecules play important roles in biological signaling in both animal and plant physiology. The hydrocarbon gas ethylene has long been known to regulate diverse aspects of plant growth and development, including fruit ripening, leaf senescence and flower abscission. Recent progress has been made toward identifying components involved in ethylene signal transduction in the plant Arabidopsis thaliana. Ethylene is perceived by five receptors that have similarity to two‐component signaling proteins. The hydrophobic amino‐terminus of the receptors binds ethylene, and mutations (...) in this domain both prevent ethylene binding and confer ethylene insensitivity to the plant; the carboxyl‐terminal portion of the receptors has similarity to bacterial his tidine protein kinases. Genetic data suggest a model in which ethylene binding inhibits receptor signaling, yet precisely how these receptors function is unclear. Two of the receptors have been found to associate with a negative regulator of ethylene responses called CTR1, which appears to be a mitogen‐activated protein kinase (MAPK) kinase kinase. BioEssays 23:619–627, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The T lymphocyte receptor for antigen, which operates in conjunction with gene products of the major histocompatibility complex (MHC), is a molecular complex comprised of five polypeptide chains. Both the 49 kDa alpha and 43 kDa beta chains are immunoglobulin‐like and thus contain variable domains responsible for ligand binding. In contrast, the 20–25 kDa T3 gamma, delta and epsilon chains are monomorphic structures presumably involved in transmembrane signalling. The alpha and beta subunits are disulfide bonded to each other (...) and held in noncovalent association with the T3 chains. T3‐Ti receptor crosslinking leads to conformational modification of a second T lineage specific molecule, termed the 50 kDa T11 structure which in turn leads to protein kinase C activation, elevation in intracytoplasmic free calcium and Na+/H+ antiport stimulation. (shrink)

A fast growing family of ATPases has recently been highlighted. It was named the AAA family, for ATPases Associated to a variety of cellular Activities. The key feature of the family is a highly conserved module of 230 amino acids present in one or two copies in each protein. Despite extensive sequence conservation, the members of the family fulfil a large diversity of cellular functions: cell cycle regulation, gene expression in yeast and HIV, vesicle‐mediated transport, peroxisome assembly, 26S (...) protease function etc. In addition, several members of this family can be found in the same organism (up to 17 in S. cerevisiae). The contrast between functional diversity and structural conservation of the module, from archaebacteria to mammals, suggests that it plays an essential, but as yet unknown, role at key points of the cellular machinery. Two (non‐exclusive) such possibilities are: (1) ATP‐dependent proteasome function and (2) ATP‐dependent anchorage of proteins. Finally, the basic biochemical activity of the AAA module is still a matter of speculation, and we propose that it acts as an ATP‐dependent protein clamp. (shrink)

Deciphering how DCAFs (DDB1‐CUL4 Associated Factors) modulate a broad spectrum of cellular processes, including cell cycle progression and maintenance of genomic integrity is critical to better understand cellular homeostasis and diseases. Cells contain more than 100 DCAFs that associate with the Cullin‐Ring Ubiquitin Ligase 4 (CRL4) complex that target specific protein substrates for degradation. DCAFs are thought to act as substrate receptors that dictate the specificity of the ubiquitination machinery (“catalytic DCAFs”). However, recent studies have suggested that some (...) DCAFs might play a different role by targeting CRL4 complexes to distinct cellular compartments (“structural DCAFs”). Once localized to their correct cellular domains, these CRLs dissociate from the structural DCAFs prior to their association with other, substrate‐specific catalytic DCAFs. Thus, we propose that DCAF switches can provide a mechanistic basis for the degradation of proteins that regulate cell growth and proliferation at precise points in space and time. (shrink)

Are there sex differences in pain? For experimentally delivered somatic stimuli, females have lower thresholds, greater ability to discriminate, higher pain ratings, and less tolerance of noxious stimuli than males. These differences, however, are small, exist only for certain forms of stimulation and are affected by many situational variables such as presence of disease, experimental setting, and even nutritive status. For endogenous pains, women report more multiple pains in more body regions than men. With no obvious underlying rationale, some painful (...) diseases are more prevalent among females, others among males and, for many diseases, symptoms differ between females and males. Sex differences in attitudes exist that affect not only reporting, coping, and responses to treatment, but also measurement and treatment. So many variables are operative, however, that the most striking feature of sex differences in reported pain experience is the apparent overall lack of them. On the other hand, deduction from known biological sex differences suggests that these are powerful sex differences in the operation of pain mechanisms. First, the vaginal canal provides an additional route in women for internal trauma and invasion by pathological agents that puts them at greater risk for developing hyperalgesia in multiple body regions. Second, sex differences in temporal patterns are likely to give rise to sex differences in how pain is and stimuli are interpreted, a situation that could lead to a greater variability and wider range of pains without obvious peripheral pathology among females. Third, sex differences in the actions of sex hormones suggest pain-relevant differences in the operation of many neuroactive agents, opiate and nonopiate systems, nerve growth factor, and the sympathetic system. Thus, while inductive analysis of existing data demonstrate more similarities than differences in pain experience between females and males, deductive analysis suggests important operational sex differences in its production. (shrink)

Nicotinic acetylcholine receptors (nAChRs) are ligand‐gated ion channels that bring about a diversity of fast synaptic actions. Analysis of the Caenorhabditis elegans genome has revealed one of the most‐extensive and diverse nAChR gene families known, consisting of at least 27 subunits. Striking variation with possible functional implications has been observed in normally conserved motifs at the acetylcholine‐binding site and in the channel‐lining region. Some nAChR subunits are particular to neurons whilst others are present in both neurons and muscles. The localization (...) of subunits in non‐synaptic regions suggests novel roles for nAChRs. Genetic and heterologous expression studies have identified a subset of nAChR subunits that are important drug targets while the study of mutants has identified genes functionally‐linked to nAChRs. Future studies using C. elegans offer the prospect of increasing our understanding of the functional diversity of a complex nAChR gene family as well as addressing the role of nAChRs and associated proteins in human disorders. BioEssays 26:39–49, 2004.© 2003 Wiley Periodicals, Inc. (shrink)

Although there are probably over a thousand publications on the associations of blood groups and disease, many are based totally on statistical analyses. Most of the earlier studies have been controversial, because they were small studies and/or had inadequate controls and/or had been analyzed incorrectly. Nevertheless, it is difficult to argue with the general pattern that emerges from the large body of statistical data on malignancy, coagulation and infection. Recent findings in membrane chemistry, tumor immunology and infectious disease (especially relating (...) to bacterial receptors), add a scientific rationale for some of these findings, and there is an increasing rationale for some of the earlier statistical findings. Some of the more recent findings on parasitic/bacterial/viral receptors, the hematological abnormalities seen when high frequency blood group antigens are missing, and the association with immunologically important proteins are most convincing and suggest that blood group antigens do sometimes play a biological role; this role may relate directly, or often be completely unrelated, to the red cell. (shrink)

The secretory system of plant cells sorts a large number of soluble proteins that either are secreted or accumulate in vacuoles. Secretion is a bulk‐flow process that requires no information beyond the presence of a signal peptide necessary to enter the endoplasmic reticulum. Many vacuolar proteins are glycoproteins and the glycans are often modified as the proteins pass through the Golgi complex. Vacuolar targeting information is not contained in glycans as it is in animal cells; rather, targeting information is in (...) polypeptide domains as it is in yeast cells. Several such domains have now been identified, but these show little or no amino acid sequence homology. We discuss the possibilities that targeting of protein to plant vacuoles may involve receptors as well as aggregation of protein at low pH. (shrink)

Lysophosphatidic acid (LPA) is a lipid mediator with a wide variety of biological actions, particularly as an inducer of cell proliferation, migration and survival. LPA binds to specific G‐protein‐coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. LPA signaling has been implicated in such diverse processes as wound healing, brain development, vascular remodeling and tumor progression. Knowledge of precisely how and where LPA is produced has long proved (...) elusive. Excitingly, it has recently been discovered that LPA is generated from precursors by ‘autotaxin’, a once enigmatic exo‐phosphodiesterase implicated in tumor cell motility. Exogenous phospholipases D can also produce LPA, which may contribute to their toxicity. Here we review recent progress in our understanding of LPA bioactivity, signaling and synthesis. BioEssays 26:870–881, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

The preceding five years have brought remarkable advances in our understanding of the primary structure of drug receptors. The roles of certain amino acid residues in binding drugs and effecting receptor function have been proposed. As even more detailed structures become available, the goal of rational design of drug molecules based on predicted fits between the drug and its receptor will be near at hand. Although none of the classical receptors has yet yielded to X‐ray crystallographic analysis, (...) the methods of molecular biology facilitate the production of the large amounts of these rare proteins necessary for crystallization. Receptor proteins share one fundamental characteristic with allosterically regulated enzymes. Both have the structural flexibility that allows information to be transmitted to distant parts of the molecule. We will discuss recent observations about receptor structure and the dynamic nature of drug receptors, and pose questions about the significance of receptor dynamics for drug design. (shrink)

The immune system distinguishes between two types of antigenic sites: one of these binds to immunoglobulins (IgGs) (i.e. antibodies), while the other binds to receptor molecules on T lymphocytes (i.e. the T‐cell receptors (TcRs)). The latter interaction occurs only when the antigen is presented in association with a self‐transplantation antigen, a so‐called MHC‐restriction element. This article discusses what is known about the structure of antigenic sites and their molecular interactions with antibodies, MHC‐restriction elements, and T‐lymphocyte receptors.

Interleukin 5 (IL‐5) is a kind of peptide hormone released from T lymphocytes of mammals infected with microorganisms or parasites. It is an acidic glycoprotein with a molecular mass of 40 to 50 kDa that consists of a homodimer of polypeptides. It controls hematopoiesis so that it increases natural immunity. In the mouse, IL‐5 acts on committed B cells to induce differentiation into Ig‐producing cells and on common progenitors for CD5+ pre‐B cells and CD5+ macrophages to support their survival. The (...) antibodies secreted by CD5+ B cells seem to be responsible for the primary protection against the infection with microorganisms or parasites. It also supports the growth and/or differentiation of eosinophil precursor and mature eosinophils, which can be effective for the removal of parasites in combination with the antibodies against them. Murine IL‐5 receptor (IL‐5R) consists of two different polypeptide chains; αL chain and β chain. The IL‐5R α chain is 60 kDa protein that binds IL‐5 with low affinity. The IL‐5R β chain is a 130 kDa protein which does not bind IL‐5 by itself but is necessary to form the high affinity IL‐5R. The β chain was identified by using one of the anti‐IL‐5R mAb and anti‐IL‐3R mAb as the IL‐3R homologue. This β chain is also used as the β chain of GM‐CSF receptor. This fact suggests that there is a common signaling mechanism among these cytokines and efficient cooperation among them. At the same time, these findings may explain the overlapping role of these cytokines in the development of granulocytes. (shrink)

Disabled‐2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell–cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab‐2 controls the extent of (...) platelet aggregation through various motifs within its N‐terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside‐out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin αIIbβ3 receptor binding and, thus, modulates outside‐in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell–cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences. (shrink)

Most lymphocytes of the T cell lineage develop along the CD4/CD8 pathway and express antigen receptors on their surfaces consisting of clonotypic αβ chains associated with invariant CD3‐γδε components and ζ chains, collectively referred to as the T cell antigen receptor complex (TCR). Expression of the TCR complex is dynamically regulated during T cell development, with immature CD4+CD8+ thymocytes expressing only 10% of the number of αβ TCR complexes on their surfaces expressed by mature CD4+ and CD8+ T (...) cells. Recent evidence demonstrates that low surface TCR density on CD4+CD8+ thymocytes results from the limited survival of a single TCR component within the ER, the TCRα chain, which has a half life of only 15 minutes in immature thymocytes, compared to >75 minutes in mature T cells. Instability of TCRα proteins in immature CD4+CD8+ thymocytes represents a novel mechanism by which expression of the multisubunit TCR complex is quantitatively regulated during T cell development. In the current review we discuss our recent findings concerning the assembly, intracellular transport, and expression of αβ TCR complexes in CD4+CD8+ thymocytes and comment on the functional significance of TCRα instability during T cell development. (shrink)

The activation of leukocytes by bacterial cell wall lipopolysaccharide (LPS) contributes to the pathogenesis of septic shock. It is well established that, in the presence of plasma LPS‐binding protein (LBP), LPS binds with high affinity to CD14. The binding of LPS to CD14 has been associated with the activation of cells, although available evidence indicates that CD14 itself does not transduce intracellular signalling. The physiological function of this interaction is to promote host defense mechanisms of cells to combat (...) the infection and clear LPS from the circulation. At higher concentrations of LPS, however, the activation of cells can take place in the absence of LBP and CD14, presumably through a distinct low‐affinity signalling LPS receptor. On the evidence published by us and others, we propose that in neutrophils, and possibly other leukocytes, L‐selectin can act as a low‐affinity LPS receptor. (shrink)

The possible dysfunction of [gamma] aminobutyric acid (GABA) and opioid inhibitory mechanisms following central and peripheral nervous system injury is an important and potentially useful finding. However, effective clinical application must take into account the specific characteristics of the models used in the studies and the relationship of these models to specific clinical conditions. [dickenson; wiesenfeld-hallin et al.].

The Y‐box‐binding protein (YB‐1) represents the most evolutionary conserved nucleic‐acid‐binding protein currently known. YB‐1 is a member of the cold‐shock domain (CSD) protein superfamily. It performs a wide variety of cellular functions, including transcriptional regulation, translational regulation, DNA repair, drug resistance and stress responses to extracellular signals. As a result, YB‐1 expression is closely associated with cell proliferation. In this review, we will begin by briefly describing the characteristics of YB‐1 and will then summarize the (...) pleiotropic functions brought about via DNA–RNA transaction and protein–protein interactions. In addition, we will discuss the diverse range of potential physiological and pathological functions of YB‐1. BioEssays 25:691–698, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Cells can change their function by rapidly modulating the levels of certain proteins at the plasma membrane. This rapid modulation is achieved by using a specialised trafficking process called constitutive cycling. The constitutive cycling of a variety of transmembrane proteins such as receptors, channels and transporters has recently been directly demonstrated in a wide range of cell types. This regulation is thought to underlie important biological phenomena such as learning and memory, gastric acid secretion and water and blood glucose (...) homeostasis. This review discusses the molecular mechanisms of constitutive cycling, its regulation by extracellular agents such as hormones and its misregulation in disease states. BioEssays 25:39–46, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

Recent evidence indicates that inhibition of protein translation may be a common pathogenic mechanism for peripheral neuropathy associated with mutant tRNA synthetases (aaRSs). aaRSs are enzymes that ligate amino acids to their cognate tRNA, thus catalyzing the first step of translation. Dominant mutations in five distinct aaRSs cause Charcot‐Marie‐Tooth (CMT) peripheral neuropathy, characterized by length‐dependent degeneration of peripheral motor and sensory axons. Surprisingly, loss of aminoacylation activity is not required for mutant aaRSs to cause CMT. Rather, at least (...) for some mutations, a toxic‐gain‐of‐function mechanism underlies CMT‐aaRS. Interestingly, several mutations in two distinct aaRSs were recently shown to inhibit global protein translation in Drosophila models of CMT‐aaRS, by a mechanism independent of aminoacylation, suggesting inhibition of translation as a common pathogenic mechanism. Future research aimed at elucidating the molecular mechanisms underlying the translation defect induced by CMT‐mutant aaRSs should provide novel insight into the molecular pathogenesis of these incurable diseases. (shrink)

Sarcopenia is a process of progressive aging‐associated loss of skeletal muscle mass (SMM) recognized as a serious global health issue contributing to frailty and increased all‐cause mortality. Exercise and nutritional interventions (particularly intake of dairy products and milk) demonstrate good efficacy, safety, and broad applicability. Here, we propose that at least some of the well‐documented favorable effects of milk and milk‐derived protein supplements on SMM might be mediated by D‐galactose, a monosaccharide present in large quantities in milk in (...) the form of disaccharide lactose (milk sugar). We suggest that ingestion of dairy products results in exposure to D‐galactose in concentrations metabolized primarily via the Leloir pathway with the potential to (i) promote anabolic signaling via maintenance of growth factor (e.g., insulin‐like growth factor 1 [IGF‐1]) receptor mature glycosylation patterns; and (ii) provide extracellular (liver glycogen) and intracellular substrates for short (muscle glycolysis) and long‐term (muscle glycogen, intramyocellular lipids) energy availability. Additionally, D‐galactose might optimize the metabolic function of skeletal muscles by increasing mitochondrial content and stimulating glucose and fatty acid utilization. The proposed potential of D‐galactose to promote the accretion of SMM is discussed in the context of its therapeutic potential in sarcopenia. (shrink)

Superoxide is produced by a NADPH oxidase of phagocytic cells and contributes to their microbicidal activities. The oxidase is activated when receptors in the neutrophil plasma membrane bind to the target microbe. These receptors recognise antibodies and complement fragments which coat the target cell. The oxidase electron transport chain, located in the plasma membrane, comprises a low potential cytochrome b heterodimer (gp 91‐phox and p22‐phox) associated with FAD. It is non‐functional until at least three proteins, p67‐phox, p47‐phox and p21rac (...) (and possibly others), move from the cytosol to dock on the cytochrome b. The docking involves the interaction of SH3 domains may become exposed follwoing phosphorylation of p47‐phox by protein kinase C or, in model systems, by addition of arachidonic acid to reconstitution mixtures. Following the docking process the electron‐transporting component is able to transfer electrons from NADPH to oxygen. This electrogenic event is charge‐compensated by the opening of a prton channel. Components of the oxidase are expressed in non‐phagocytes, where their function is uncretain but could be related to some signal function of superoxide. (shrink)

Significant associations have been found between specific human leukocyte antigen (HLA) alleles and organ transplant rejection, autoimmune disease development, and the response to infection. Traditional searches for disease associations have conventionally measured risk associated with the presence of individual HLA alleles. However, given the high level of HLA polymorphism, the pattern of amino acid variability, and the fact that most of the HLA variation occurs at functionally important sites, it may be that a combination of variable amino (...) class='Hi'>acid sites shared by several alleles (shared epitopes) are better descriptors of the actual causative genetic variants. Here we describe a novel approach to genetic association analysis in which genes/proteins are broken down into smaller sequence features and then variant types defined for each feature, allowing for independent analysis of disease association with each sequence feature variant type. We have used this approach to analyze a cohort of systemic sclerosis patients and show that a sequence feature composed of specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk for systemic sclerosis. (shrink)

Transcranial magnetic stimulation studies have demonstrated increased cortical facilitation and reduced inhibition following aerobic exercise, even when examining motor regions separate to the exercised muscle group. These changes in brain physiology following exercise may create favorable conditions for adaptive plasticity and motor learning. One candidate mechanism behind these benefits is the increase in brain-derived neurotropic factor observed following exercise, which can be quantified from a venous blood draw. The aim of this study was to investigate changes in motor cortex excitability (...) and inhibition of the upper limb, and circulating BDNF, following high-intensity interval training on a stationary bicycle. Nineteen sedentary adults participated in a randomized crossover design study involving a single bout of high-intensity interval cycling for 20 min or seated rest. Venous blood samples were collected, and transcranial magnetic stimulation was used to stimulate the extensor carpi radialis, where motor evoked potentials were recorded pre- and post-condition. Following exercise, there was a significant increase in corticospinal excitability measured at 120% of resting motor threshold and a reduction in short-interval cortical inhibition. There was a non-significant 23.6% increase in BDNF levels. Collectively, these results reflect a net reduction in gamma aminobutyric acid ergic synaptic transmission and increased glutamatergic facilitation, resulting in increased corticospinal excitability. This study supports the notion that acute high-intensity exercise provides a potent stimulus for inducing cortical neuroplasticity, which may support enhanced motor learning. (shrink)

Deep brain stimulation is a clinical intervention for the treatment of movement disorders. It has also been applied to the treatment of psychiatric disorders such as depression, anorexia nervosa, obsessive-compulsive disorder, and schizophrenia. Psychiatric disorders including schizophrenia, bipolar disorder, and major depression can lead to psychosis, which can cause patients to lose touch with reality. The ventral tegmental area, located near the midline of the midbrain, is an important region involved in psychosis. However, the clinical application of electrical stimulation of (...) the VTA to treat psychotic diseases has been limited, and related mechanisms have not been thoroughly studied. In the present study, hyperlocomotion and stereotyped behaviors of the mice were employed to mimic and evaluate the positive-psychotic-like behaviors. We attempted to treat positive psychotic-like behaviors by electrically stimulating the VTA in mice and exploring the neural mechanisms behind behavioral effects. Local field potential recording and in vivo fiber photometry to observe the behavioral effects and changes in neural activities caused by DBS in the VTA of mice. Optogenetic techniques were used to verify the neural mechanisms underlying the behavioral effects induced by DBS. Our results showed that electrical stimulation of the VTA activates local gamma-aminobutyric acid neurons, and dopamine neurons, reduces hyperlocomotion, and relieves stereotyped behaviors induced by MK-801 injection. The results of optogenetic manipulation showed that the activation of the VTA GABA neurons, but not DA neurons, is involved in the alleviation of hyperlocomotion and stereotyped behaviors. We visualized changes in the activity of specific types in specific brain areas induced by DBS, and explored the neural mechanism of DBS in alleviating positive psychotic-like behaviors. This preclinical study not only proposes new technical means of exploring the mechanism of DBS, but also provides experimental justification for the clinical treatment of psychotic diseases by electrical stimulation of the VTA. (shrink)