The direction and specificity of endolysosomal membrane trafficking is tightly regulated by various cytosolic and membrane‐bound factors, including soluble NSF attachment protein receptors (SNAREs), Rab GTPases, and phosphoinositides. Another trafficking regulatory factor is juxta‐organellar Ca2+, which is hypothesized to be released from the lumen of endolysosomes and to be present at higher concentrations near fusion/fission sites. The recent identification and characterization of several Ca2+ channel proteins from endolysosomal membranes has provided a unique opportunity to examine the roles of Ca2+ (...) and Ca2+ channels in the membrane trafficking of endolysosomes. SNAREs, Rab GTPases, and phosphoinositides have been reported to regulate plasma membrane ion channels, thereby suggesting that these trafficking regulators may also modulate endolysosomal dynamics by controlling Ca2+ flux across endolysosomal membranes. In this paper, we discuss the roles of phosphoinositides, Ca2+, and potential interactions between endolysosomal Ca2+ channels and phosphoinositides in endolysosomal dynamics. (shrink)

Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface‐localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease. Supporting this hypothesis is our (...) recent work demonstrating direct physical and bidirectional functional interactions of TRPV4 with RhoA, which can lead to activation of RhoA and reorganization of the actin cytoskeleton. Furthermore, a confluence of evidence implicates TRPV4 and/or RhoA in pathological responses triggered by a range of acute neurological insults ranging from stroke to traumatic injury. While initiated by a variety of insults, TRPV4–RhoA signaling may represent a common pathway that disrupts axonal regeneration and blood–brain barrier integrity. These insights also suggest that TRPV4 inhibition may represent a safe, feasible, and precise therapeutic strategy for limiting pathological TRPV4–RhoA activation in a range of neurological diseases. (shrink)

In this review, we introduce the concept of “dual thermosensing mechanisms,” highlighting the functional collaboration between G protein‐coupled receptors (GPCRs) and transient receptor potential (TRP) channels that enable sophisticated cellular thermal responsiveness. GPCRs have been implicated in thermosensory processes, with recent findings identifying several candidates across species, including mammals, fruit flies, and nematodes. In many cases, these GPCRs work in conjunction with another class of thermosensors, TRP channels, offering insights into the complex mechanisms underlying thermosensory signaling. We (...) examine how GPCRs function as thermosensors and how their signaling regulates cellular thermosensation, illustrating the complexity of thermosensory systems. Understanding these dual thermosensory mechanisms would advance our comprehension of cellular thermosensation and its regulatory pathways. (shrink)

A new high‐resolution structure of a pain‐sensing ion channel, TRPA1, provides a molecular scaffold to understand channel function. Unexpected structural features include a TRP‐domain helix similar to TRPV1, a novel ligand‐binding site, and an unusual C‐terminal coiled coil stabilized by inositol hexakisphosphate (IP6). TRP‐domain helices, which structurally act as a nexus for communication between the channel gates and its other domains, may thus be a feature conserved across the entire TRP family and, possibly, other allosterically‐gated channels. Similarly, (...) the TRPA1 antagonist‐binding site could also represent a druggable location in other ion channels. Combined with known TRPA1 functional properties, the structural role for IP6 leads us to propose that polyphosphate unbinding could act as a molecular kill switch for TRPA1 inactivation. Finally, although packing of the TRPA1 membrane‐proximal region hints at a mechanism for electrophile sensing, the details of how TRPA1 responds to noxious reactive electrophiles and temperature await future studies.Also watch the Video Abstract. (shrink)

For almost 30 years the ion channel that initiates the ON visual pathway in vertebrate vision has remained elusive. Recent findings now indicate that the pathway, which begins with unbinding of glutamate from the metabotropic glutamate receptor 6 (mGluR6), ends with the opening of the transient receptor potential (TRP)M1 cation channel. As a component of the mGluR6 signal transduction pathway, mutations in TRPM1 would be expected to cause congenital stationary night blindness (CSNB), and several (...) such mutations have already been identified in CSNB families. Furthermore, expression of TRPM1 in both the retina and skin raises the possibility that a genetic link exists between certain types of visual and skin disorders. (shrink)

Chloride channels are probably found in every cell, from bacteria to mammals. Their physiological tasks range from cell volume regulation to stabilization of the membrane potential, signal transduction, transepithelial transport and acidification of intracellular organelles. These different functions require the presence of many distinct chloride channels, which are differentially expressed and regulated by various stimuli. These include various intracellular messengers (like calcium and cyclic AMP), pH, extracellular ligands and transmembrane voltage. Three major structural classes of chloride channels are known (...) to date, but there may be others not yet identified. After an overview of the general functions of chloride channels, this review will focus on these cloned chloride channels: the CLC chloride channel family, which includes voltage‐gated chloride channels, and the cystic fibrosis transmembrane regulator (CFTR), which performs other functions in addition to being a chloride channel. Finally, a short section deals with GABA and glycine receptors. Diseases resulting from chloride channel defects will be specially emphasized, together with the somewhat limited information about how these proteins work at the molecular level. (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)

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, (...) L‐glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy. (shrink)

A theory of anaesthesia is presented. It consists of four hypotheses: (1) The occurrence of states of consciousness causally depends on the formation of transient higher-order, self-referential mental representations. The occurrence of such states is identical with the appearance of conscious phenomena. Loss of consciousness will occur, if and only if the brain's representational activity falls below a critical threshold. (2) Mental representations are instantiated by neural cell assemblies. (3) The formation of assemblies involves the activation of the NMDA (...) receptor channel complex. The activation state of this receptor determines the rate at which assemblies are generated. (4) General anaesthetics have a common operative mechanism: they directly or indirectly affect the function of the NMDA system. (shrink)

Neuropeptides are key modulators of adult neurocircuits, balancing their sensitivity to both excitation and inhibition, and fine‐tuning fast neurotransmitter action under physiological conditions. Here, we reason that transient increases in neuropeptide availability and action exist during brain development for synapse maturation, selection, and maintenance. We discuss fundamental concepts of neuropeptide signaling at G protein‐coupled receptors (GPCRs), with a particular focus on how signaling at neuropeptide GPCRs could underpin neuronal morphogenesis. We use galanin, a 29/30 amino acid‐long neuropeptide, as an (...) example for its retrograde release from the dendrites of thalamic neurons to impact the selection and wiring of sensory afferents originating at the trigeminal nucleus through galanin receptor 1 (GalR1) engagement. Thus, we suggest novel roles for neuropeptides, expressed transiently or permanently during both pre‐ and postnatal neuronal circuit development, with potentially life‐long effects on circuit layout and ensuing behavioral operations. (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)

We have discovered that a single sperm protein, phospholipase C‐zeta (PLCζ), can stimulate intracellular Ca2+ signalling in the unfertilized oocyte (‘egg’) culminating in the initiation of embryonic development. Upon fertilization by a spermatozoon, the earliest observed signalling event in the dormant egg is a large, transient increase in free Ca2+ concentration. The fertilized egg responds to the intracellular Ca2+ rise by completing meiosis. In mammalian eggs, the Ca2+ signal is delivered as a train of long‐lasting cytoplasmic Ca2+ oscillations that (...) begin soon after gamete fusion and persist beyond the completion of meiosis. Sperm PLCζ effects Ca2+ release from egg intracellular stores by hydrolyzing the membrane lipid PIP2 and consequent stimulation of the inositol 1,4,5‐trisphosphate (InsP3) receptor Ca2+‐signalling pathway, leading to egg activation and early embryogenesis. Recent advances have refined our understanding of how PLCζ induces Ca2+ oscillations in the egg and also suggest its potential dysfunction as a cause of male infertility. (shrink)

Membrane proteins possess certain features that make them susceptible to the electric fields generated at the level of the plasma membrane. A reappraisal of cell signalling, taking into account the protein interactions with the membrane electrostatic profile, suggests that an electrical dimension is deeply involved in this fundamental aspect of cell biology. At least three types of potentials can contribute to this dimension: (1) the potential across the compact layer of water adherent to membrane surfaces; this potential is (...) affected by classical inducers of cell differentiation, like dimethylsulfoxide and hexamethylenebisacetamide; (2) the potential across the Gouy‐Chapman double layer, which accounts for the effects of extracellular cations in the modulation of differentiation; and (3) the resting potential. This last potential and its governing ion currents can be exploited in localised mechanisms of cell signalling centred on the functional association of integrin receptors with ion channels. (shrink)

IntroductionApproaches to improve heart rate variability and reduce stress such as breathing retraining are more frequently being integrated into psychotherapy but little research on their effectiveness has been done to date. Specifically, no studies to date have directly compared using a breathing pacer at 6 breaths per minute with compassion focused soothing rhythm breathing.Current StudyIn this randomized controlled experiment, 6 breaths per minute breathing using a pacer was compared with compassion focused soothing rhythm breathing, with a nature video being used (...) as a control group condition.MethodsHeart rate variability measures were assessed via electrocardiogram and respiration belt, and an automated blood pressure machine was used to measure systolic diastolic blood pressure, and heart rate. A total of 96 participants were randomized into the three conditions. Following a 5-min baseline, participants engaged in either 6 breath per minute breathing, soothing rhythm breathing, or watched a nature video for 10 min. To induce a stressful state, participants then wrote for 5 min about a time they felt intensely self-critical. Participants then wrote for 5 min about a time they felt self-compassionate, and the experiment ended with a 10-min recovery period.ResultsConditions did not significantly differ at baseline. Overall, HRV, as measured by standard deviation of NN intervals, low frequency HRV, and LF/HF ratio, increased during the intervention period, decreased during self-critical writing, and then returned to baseline levels during the recovery period. High frequency HRV was not impacted by any of the interventions. The participants in the 6 breath per minute pacer condition were unable to consistently breathe at that rate and averaged about 12 breaths per minute. Time by Condition analyses revealed that both the 6 breaths per minute pacer and soothing breathing rhythm conditions lead to significantly higher SDNN than the nature video condition during breathing practice but there were no significant differences between conditions in response to the self-critical and self-compassionate writing or recovery periods. The 6 breath per minute pacer condition demonstrated a higher LF HRV and LF/HF ratio than the soothing rhythm breathing condition, and both intervention conditions had a higher LF HRV and LF/HF ratio than the nature video.ConclusionsAlthough the 6 breath per minute pacer condition participants were not able to breath consistently at the low pace, both the participants attempting to breathe at 6 breaths per minute as well as those in the soothing rhythm breathing condition effectively increased HR variability as measured by SDNN, and attempting to breathe at 6 breaths per minute led to the highest LF HRV and LF/HF ratio. Both breathing approaches impacted HRV more than watching a relaxing nature video and can potentially be used as key adjuncts in psychotherapy to aid in regulating physiological functioning, although it appears that consistent breathing practice would be needed. (shrink)

Recent insights reveal the significant role of TRPV3 in warmth sensation. A novel finding elucidated how thermosensation is affected by TRPV3 membrane abundance that is modulated by the transmembrane protein TMEM79. TRPV3 is a warmth‐sensitive ion channel predominantly expressed in epithelial cells, particularly skin keratinocytes. Multiple studies investigated the roles of TRPV3 in cutaneous physiology and pathophysiology. TRPV3 activation by innocuous warm temperatures in keratinocytes highlights its significance in temperature sensation, but whether TRPV3 directly contributes to warmth sensations in (...) vivo remains controversial. This review explores the electrophysiological and structural properties of TRPV3 and how modulators affect its intricate regulatory mechanisms. Moreover, we discuss the multifaceted involvement of TRPV3 in skin physiology and pathology, including barrier formation, hair growth, inflammation, and itching. Finally, we examine the potential of TRPV3 as a therapeutic target for skin diseases and highlight its diverse role in maintaining skin homeostasis. (shrink)

The complete sequencing of the genome of the fruit fly Drosophila melanogaster offers the prospect of detailed functional analysis of the extensive gene families in this genetic model organism. Comprehensive functional analysis of family members is facilitated by access to a robust, stable and inducible expression system in a fly cell line. Here we show how the Schneider S2 cell line, derived from the Drosophila embryo, provides such an expression system, with the bonus that radioligand binding studies, second messenger assays, (...) ion imaging, patch‐clamp electrophysiology and gene silencing can readily be applied. Drosophila is also ideal for the study of new control strategies for insect pests since the receptors and ion channels that many new animal health drugs and crop protection chemicals target can be expressed in this cell line. In addition, many useful orthologues of human disease genes are emerging from the Drosophila genome and the study of their functions and interactions is another area for postgenome applications of S2 cell lines. BioEssays 24:1066–1073, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Transient global amnesia is a benign memory disorder with etiologies that have been debated for a long time. The prevalence of stressful events before a TGA attack makes it hard to overlook these precipitating factors, given that stress has the potential to organically effect the brain. Cortical spreading depression was proposed as a possible cause decades ago. Being a regional phenomenon, CSD seems to affect every aspect of the micro-mechanism in maintaining the homeostasis of the central nervous system. (...) Corresponding evidence regarding hemodynamic and morphological changes from TGA and CSD have been accumulated separately, but the resemblance between the two has not been systematically explored so far, which is surprising especially considering that CSD had been confirmed to cause secondary damage in the human brain. Thus, by deeply delving into the anatomic and electrophysiological properties of the CNS, the CSD-TGA model may render insights into the basic pathophysiology behind the façade of the enigmatic clinical presentation. (shrink)

Plasma membranes are subject to continuous deformations. Strikingly, some of these transient membrane undulations yield membrane‐associated signaling hubs that differ in composition and function, depending on membrane geometry and the availability of co‐factors. Here, recent advancements on this ubiquitous type of receptor‐independent signaling are reviewed, with a special focus on emerging concepts and technical challenges associated with studying these elusive signaling sites.

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)

Long‐term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP, but central amongst them is an increased sensitivity of the postsynaptic membrane to neurotransmitter release. This sensitivity is predominantly determined by the abundance and localization of AMPA‐type glutamate receptors (AMPARs). A combination of AMPAR structural data, super‐resolution imaging of excitatory synapses, and an abundance of electrophysiological studies are providing an ever‐clearer picture of how AMPARs are (...) recruited and organized at synaptic junctions. Here, we review the latest insights into this process, and discuss how both cytoplasmic and extracellular receptor elements cooperate to tune the AMPAR response at the hippocampal CA1 synapse. (shrink)

Electrical signaling by neurons depends on the precisely ordered distribution of a wide variety of ion channels on the neuronal surface. The mechanisms underlying the targeting of particular classes of ion channels to specific subcellular sites are poorly understood. Recent studies have identified a new class of protein‐protein interaction mediated by PDZ domains, protein binding modules that recognize specific sequences at the C terminus of membrane proteins. The PDZ domains of a family of synaptic cytoskeleton‐associated proteins, typified by PSD‐95, bind (...) to the intracellular C‐terminal tails of NMDA receptors and Shaker‐type K+ channels. This interaction appears to be important in the clustering and localization of these ion channels at synaptic sites. Recognition of specific C‐terminal peptide sequences by different PDZ domain‐containing proteins may be a general mechanism for differential targeting of proteins to a variety of subcellular locations. (shrink)

Urokinase and its receptor are essential components of the cell migration machinery, providing an inducible, transient and localized cell surface proteolytic activity. This activity has been shown to be required in normal and pathological forms of cellular invasiveness (i.e. in several embryonic developmental processes, during inflammatory responses and cancer metastasis and spreading). It represents one of the best known of the protcolytic systems which are currently under investigation in this field. The urokinase receptor allows a continuous regulation (...) of the proteolytic activity at cell contacts, utilizing the different localization of urokinase and its inhibitors. The receptor, in fact, in addition to focusing the enzymatic activity at focal and cell‐cell contacts, also regulates it by internalizing and degrading only the inhibited form of urokinase. Internalized receptor releases the ligands to the lysosomes and recycles back to surface. In this way, the proteolytically active areas of the cell surface can be continuously monitored for their activity and their location modified. The cell can thus coordinate its migration efforts with a step‐wise modification of the proteolytic activity‐map of the cell surface. The urokinase cycle can be supported by one individual cell (autocrine) or by two or more cells. In the latter case, complementation and synergism of urokinase and its receptor are found. (shrink)

Oligodendrocytes are known to express Ca2+-permeable glutamate receptors and to have low resistance to oxidative stress, two factors that make them potentially susceptible to injury. Oligodendrocyte injury is intrinsic to the loss of function experienced in conditions ranging from cerebral palsy to spinal cord injury, focal ischaemia and multiple sclerosis. NMDA receptors, a subtype of glutamate receptors, are vital to the remodeling of synaptic connections during postnatal development and associative learning abilities in adults and possibly in improvements in oligodendrocyte function. (...) Previous studies had failed to detect NMDA receptor mRNA or current in oligodendrocytes but three new papers1-3 demonstrate NMDA receptor expression in oligodendrocytes and discuss its implications for ischaemia therapy. BioEssays 28: 460–464, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

It was, until recently, accepted that the two classes of acetylcholine (ACh) receptors are distinct in an important sense: muscarinic ACh receptors signal via heterotrimeric GTP binding proteins (G proteins), whereas nicotinic ACh receptors (nAChRs) open to allow flux of Na+, Ca2+, and K+ ions into the cell after activation. Here we present evidence of direct coupling between G proteins and nAChRs in neurons. Based on proteomic, biophysical, and functional evidence, we hypothesize that binding to G proteins modulates the activity (...) and signaling of nAChRs in cells. It is important to note that while this hypothesis is new for the nAChR, it is consistent with known interactions between G proteins and structurally related ligand‐gated ion channels. Therefore, it underscores an evolutionarily conserved metabotropic mechanism of G protein signaling via nAChR channels.Also watch the Video Abstract. (shrink)

One potentially ethically relevant feature of an utterance is that utterance's influence on the likelihoods that our future discourses wind up with one Stalnakerian ‘common ground’ or body of shared information rather than another. Such likelihoods matter ethically, so the ways our utterances influence them can matter ethically, despite the fact that such influences are often unintended, and often hard to see. By offering a relatively neutral descriptive framework that can enhance our collective sensitivity to and discussion of ethically, socially, (...) and politically important features of language use, this paper contributes to the ethics of language use. It discusses ways in which utterances can influence the likelihoods of future common grounds by deploying one system of categorization rather than another, and argues that language’s effects on the evolution of discourse can affect the paths to and probabilities of different sorts of consensus. (shrink)

Media is the principal source of public information, and people's trust in news has been a critical mechanism in social cohesion. In recent years, the vast growth of new media has brought huge change to the way information is conveyed, cannibalizing much of the space of traditional media. This has led to renewed attention on media credibility. The study aims to explore the impact of media channel on trust in news and examine the role of news type. Twenty-six participants (...) were asked to make trust–distrust decisions after reading a variety of news headlines from different media channels while undergoing electroencephalography monitoring. The electrophysiological results showed that, for hard news, the new media condition elicited smaller N100 and larger P200 amplitudes than the traditional media condition. However, for soft news, there was no significant difference. The study suggests that the fitness of media channel and news type may influence the evaluation of news, impacting participants' affective arousal and attention allocation in the early stage and influencing trust in news. These results provide neurocognitive evidence of individuals' trust toward hard and soft news consumed via different media channels, yielding new insights into trust in media and contributing to media trust theory. (shrink)

Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron tunneling (...) was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands’ vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels. (shrink)

The osmotic activity produced by internal, non‐permeable, anionic nucleic acids and metabolites causes a persistent and life‐threatening cell swelling, or cellular edema, produced by the Gibbs‐Donnan effect. This evolutionary‐critical osmotic challenge must have been resolved by LUCA or its ancestors, but we lack a cell‐physiology look into the biophysical constraints to the solutions. Like mycoplasma, early cells conceivably preserved their volume with Cl−, Na+, and K+‐channels, Na+/H+‐exchangers, and a light‐dependent bacteriorhodopsin‐like H+‐pump. Here, I simulated protocells having these ionic‐permeabilities and inhabiting (...) an oceanic pond before the Great‐Oxygenation‐Event. Protocells showed better volume control and stable resting potentials at lower external pH and higher temperatures, favoring a certain type of extremophile life. Prevention of Na+‐influx at night, with low bacteriorhodopsin activity, required deep shutdown of highly voltage‐sensitive Na+‐channels and extremely selective K+‐channels, two conserved features essential for modern neuronal encoding. The Gibbs‐Donnan effect universality implies that extraterrestrial cells, if they exist, may reveal similar volume‐controlling mechanisms. (shrink)

Disorders of consciousness (DoC)—that is, unresponsive wakefulness syndrome/vegetative state and minimally conscious state—are debilitating conditions for which no reliable markers of consciousness recovery have yet been identified. Evidence points to the GABAergic system being altered in DoC, making it a potential target as such a marker.

We explore the potential of using magnetic cues as a novel approach to modulating ion channel expression, which could provide an alternative to traditional pharmacological interventions. Ion channels are crucial targets for pharmacological therapies, and ongoing research in this field continues to introduce new methods for treating various diseases. However, the efficacy of ion channel drugs is often compromised by issues such as target selectivity, leading to side effects, toxicity, and complex drug interactions. These challenges, along with (...) problems like drug resistance and difficulties in crossing biological barriers, highlight the need for innovative strategies. In this context, the proposed use of magnetic cues to modulate ion channel expression may offer a promising solution to address these limitations, potentially improving the safety and effectiveness of treatments, particularly for long‐term use. Key developments in this area are reviewed, the relationships between changes in ion channel expression and magnetic fields are summarized, knowledge gaps are identified, and central issues relevant to future research are discussed. (shrink)

The c‐ros, c‐met and c‐neu genes encode receptor‐type tyrosine kinases and were originally identified because of their oncogenic potential. However, recent progress in the analysis of these receptors and their respective ligands indicate that they do not mediate exclusively mitogenic signals. Rather, they can induce cell movement, differentiation or morphogenesis of epithelial cells in culture. Interestingly, the discussed receptors are expressed in embryonal epithelia, whereas direct and indirect evidence shows that the corresponding ligands are produced in mesenchymal cells. (...) In development, signals given by mesenchymal cells are major driving forces for differentiation and morphogenesis of epithelia; embryonal epithelia are generally unable to differentiate without the appropriate mesenchymal factors. The observed activities of these receptor/ligand systems in cultured cells and their expression patterns indicate that they regulate epithelial differentiation and morphogenesis also during embryogenesis and suggest thus a molecular basis for mesenchymal epithelial interactions. (shrink)

Gap junction intercellular communication channels permit the exchange of small regulatory molecules and ions between neighbouring cells and coordinate cellular activity in diverse tissue and organ systems. These channels have short half‐lives and complex assembly and degradation pathways. Much of the recent work elucidating gap junction biogenesis has featured the use of connexins (Cx), the constituent proteins of gap junctions, tagged with reporter proteins such as Green Fluorescent Protein (GFP) and has illuminated the dynamics of channel assembly in live (...) cells by high‐resolution time‐lapse microscopy. With some studies, however, there are potential short‐comings associated with the GFP chimeric protein technologies. A recent report by Gaietta et al., has highlighted the use of recombinant proteins with tetracysteine tags attached to the carboxyl terminus of Cx43, which differentially labels ‘old’ and ‘new’ connexins thus opening up new avenues for studying temporal and spatial localisation of proteins and in situ trafficking events.1 BioEssays 24:876–880, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Androgens (testosterone), acting via the androgen receptor (AR) a nuclear transcription factor, regulate male sexual development and body composition. In addition, AR expression plays an important role in the proliferation of human prostate cancer and confers a better prognosis in breast cancer. AR mRNA stability is central to the regulation of AR expression in prostate and breast cancer cells, and recent studies have demonstrated binding by members of the ELAV/Hu and poly(C) RNA‐binding protein families to a highly conserved UC‐rich (...) element in the 3′‐untranslated region of AR mRNA, with functional impact on AR protein expression. Remarkably, a CAG trinucleotide repeat in exon 1 of the AR, the length of which has been linked to prostate cancer survival, is also a target for multiple RNA‐binding proteins from a variety of human and murine tissues. In this review, we will detail the current knowledge of the mechanisms involved in regulating AR mRNA stability, the nature, potential role and structural biology of several novel AR mRNA–protein interactions, and the implications for novel therapeutics in human prostate cancer. BioEssays 26:672–682, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

SUR2, similar to SUR1, is a regulatory subunit of the ATP‐sensitive potassium channel (KATP), which plays a key role in numerous important physiological processes and is implicated in various diseases. Recent structural studies have revealed that, like SUR1, SUR2 can undergo ligand‐dependent dynamic conformational changes, transitioning between an inhibitory inward‐facing conformation and an activating occluded conformation. In addition, SUR2 possesses a unique inhibitory Regulatory helix (R helix) that is absent in SUR1. The binding of the activating Mg‐ADP to NBD2 (...) of SUR2 competes with the inhibitory Mg‐ATP, thereby promoting the release of the R helix and initiating the activation process. Moreover, the signal generated by Mg‐ADP binding to NBD2 might be directly transmitted to the TMD of SUR2, prior to NBD dimerization. Furthermore, the C‐terminal 42 residues (C42) of SUR2 might allosterically regulate the kinetics of Mg‐nucleotide binding on NBD2. These distinctive properties render SUR2 intricate sensors for intracellular Mg‐nucleotides. (shrink)

Disturbances of consciousness, including fluctuations in attention and awareness, are a common and clinically important symptom in dementia with Lewy bodies. In the present study we investigate potential mechanisms of such disturbances of consciousness in a clinicopathological study evaluating specific components of the cholinergic system. [3H]Epibatidine binding to the high-affinity nicotinic receptor in the temporal cortex differentiated DLB cases with and without DOC, being 62–66% higher in those with DOC. The were no differences between DLB patients with or (...) without DOC in 125I-labeled α-bungaratoxin binding to the low-affinity nicotinic receptor, [3H]pirenzepine binding to the muscarinic M1 receptor, or in choline acetyltransferase activity. These findings provide support for the hypothesis that cholinergic activity is an important neural correlate if consciousness and suggest a mechanism of DOC in DLB involving alterations in the nicotinic receptor, composed of predominantly α4 and β2 subunits. (shrink)

With the aim of giving a naturalistic foundation to the notion of mental representation, Fred Dretske (1981;1988) has put forward and developed the idea that the relation between a representation and its intentional content is grounded on an informational relation. In this explanatory model, mental representations are conceived of as states of organisms which a learning process has selected to play a functional role: a necessary condition for fulfilling this role is that the organism or some proper part of it (...) (presumably situated in the brain) is a natural indicator of the occurrence of a determinate type of event in the environment of the organism (or in the organism but outside of the proper part serving as the indicator). A state of the organism is a natural indicator of a type of event if and only if it carries information about the occurrence of that type of event. Jerry Fodor (1987) has devised and followed another strategy which consists in considering the relation between a mental representation and its intentional object as a relation of lawful, or nomic, dependence. A representational state of an organism has an objective content in virtue of the existence of a relation of nomic dependence between this state - presumably a property of the brain of the organism - and some objective property in the world. This dependence also creates a regular correlation between the occurrences of representational states of a certain type and the states of affairs whose type is their representational content. Both approaches encounter indeterminacy problems: for each, there exist situations in which the explanatory model chosen - information flow or nomic dependence - does not succeed in selecting, purely on the basis of the constraints characteristic of that model, one out of several potential contents for a given representational state. In such cases, that state is related to more than one type of events in accordance with the informational or nomic constraints imposed by those theories. In what follows, I examine an attempt by Pierre Jacob (1997) to solve two problems of indeterminacy threatening the informational theory of mental representation. According to Jacob, one of these problems can be solved with the help of the distinction between the source which is the target of the information and the channel over which the information is transmitted, whereas the solution to the other problem requires the introduction of the concept of function. I shall begin with a consideration of the distinction, with respect to a situation of information transmission, between the source and the channel. I argue that both the source and the channel, and thus the information transmitted, depend not only on the external situation which characterises the source, the channel and the receiving organism, but also on the previous knowledge and the informational needs of the receiver. I then try to show that this relativity of information undermines the solution Jacob proposes to one of the problems of indeterminacy of representational content. Finally, I examine the possibility considered by Dretske and Jacob to solve this 'problem of the reference class' due to the mentioned relativity of information, by grounding the flow of information on lawful dependence instead of statistical dependence. I shall propose two arguments showing first that these two groundings are not equivalent and second that nomic dependence is inappropriate as a grounding for information flow. I conclude by suggesting that the problem of the reference class can be solved within the framework of the informational approach, on the condition of enriching it with functional considerations. (shrink)

Rare copy number variants have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large CNVs at several loci, including microdeletions at 1q21.1, 3q29, 15q13.3 and 22q11.2 and microduplication at 16p11.2. However, these CNVs collectively account for a small fraction of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy (...) number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 patients versus 2 of 7,431 controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. © 2011 Macmillan Publishers Limited. All rights reserved. (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)

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that (...) the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory. (shrink)

Defects of growth inhibitory pathways have an important role in disorders of cell growth and differentiation. The discovery of a mutation in one of the principle components of the transforming growth factor β (TGFβ) receptor system which is linked to a DNA repair defect(1) represents one possible mechanism of escape from negative regulatory influences acting upon cells. TGFβ is a pre‐eminent negative growth factor and this article discusses (1) the role of TGFβ in maintaining epithelial homeostasis; (2) how breakdown (...) of inhibitory pathways can promote neoplastic development; (3) the significance of a receptor defect in a negative signalling pathway; and (4) the potential therapeutic sequelae resulting from restoration of cellular responsiveness to TGFβ. (shrink)

In our reply to critiques of our GLP-1 receptor agonist allocation framework, we explain that using potential years of life lost (PYLL) as a metric addresses racial health disparities without explicitly allocating resources based on race. This approach is "racism-conscious" and has legal and ethical challenges over race-based approaches. Meanwhile, though acknowledging the importance of cardiovascular risk assessment, we maintain in response to other interlocutors that focusing solely on immediate risk would ignore the broader goal of mitigating disadvantage. (...) We emphasize that our framework balances multiple ethical objectives beyond just maximizing medical benefits. (shrink)

Directed cell migration is a fundamental component of numerous biological systems and is critical to the pathology of many diseases. Although the importance of secreted chemoattractant factors in providing navigational cues to migrating cells bearing specific chemoattractant receptors is now well‐established, how the function of these factors is regulated is not so well understood and may be of key importance to the design of new therapeutics for numerous human diseases. While regulation of migration clearly takes place on a number of (...) different levels, it is becoming clear that so‐called ‘atypical’ receptors play a role in scavenging, or altering the localisation of, chemoattractant molecules such as chemokines and complement components. These receptors do this through binding and/or internalising their chemoattractant ligands without activating signal transduction cascades leading to cell migration. The atypical chemokine receptor family currently comprises the receptors D6, DARC and CCX‐CKR. In this review, we discuss the evidence from in vitro and in vivo studies that these receptors play a role in regulating cell migration, and speculate that other orphan receptors may also belong to this family. Furthermore, with the advent of gene therapy on the horizon, the therapeutic potential of these receptors in human disease is also considered. BioEssays 29: 237–247, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In the present study we investigated the role of channel characteristics with regard to gender role portrayals in television advertisements. Drawing on cultivation theory and social cognitive theory, we investigated six key variables in this line of research. We sampled a total of N = 1022 advertisements from four Austrian television channels: a public service channel, a commercial channel, and one commercial special interest channel for men and for women, respectively. Our results replicate well-known stereotypic gender (...) role portrayals prevalent in television advertisements. The public service channel and the private channel did not differentiate from each other with regards to gender stereotyping. We found that a channel with a female target group aired advertisements containing the same or even amplified stereotypes compared to a male channel. The potential negative effects of stereotypic gender role portrayals in television advertisements are discussed. (shrink)

Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury. Established neuropathic pain was reversed by intrathecally delivered TLR4 (...) class='Hi'>receptor antagonists derived from lipopolysaccharide. Additionally, -naltrexone, -naloxone, and -naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by -naloxone and -naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists -naloxone and -naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with -naloxone is of potential clinical relevance. This is because -naloxone is an antagonist that is inactive at the -opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that -opioid antagonists such as -naloxone may be useful clinically to suppress glial activation, yet -opioid agonists suppress pain. (shrink)

Online shopping for customized garments has become the fastest-growing field of the Chinese eBusiness market. Most consumers not only limit themselves to buying standardized garments but also want to buy garments customized to their preferences. This phenomenon has pushed the fashion textile and apparel industry to change its supply chain operations to meet the customization demand. Besides, the fashion textile and apparel industry also want to study how different channel factors will affect consumers' perceived value and further influence consumers' (...) purchasing decisions. We initiated this study and empirically tested more than 200 experienced consumers. This study collaborated with a fashion textile and apparel company that aims to implement customized product lines soon. Based on the perceived value theory and risk management theory, we investigated whether product involvement and channel identification on supply chain design will affects potential customized product consumers' purchasing decisions. The findings reveal that channel recognition affects consumer decisions by having a positive impact on their perceived value. The perceived risk and shopping channel involvement of consumers have a negative impact on their perceived values and channel selections. In addition, product involvement has a moderating effect on the relationship between channel's perceived risk, perceived values, and channel selections as well. (shrink)

Focusing on the dual-channel supply chain with live broadcasts selling, this paper investigates the service overflow of live broadcasts with Stackelberg game perspective and the impact of retailers’ different market potentials on the pricing decisions of dual-channel members. Meanwhile, it also evaluates the pricing strategy of online retailers after introducing KOL live broadcasts. The results show that when one of the dual-channel retailers adopts live broadcast sales, the live broadcast service overflow will have an adverse impact on (...) it, but the degree of the impact depends on the market potential of supply chain members, and different power structures can be used to offset the adverse impact of live broadcast service overflow. Then, the live broadcast sales service overflow will have a certain beneficial impact on online retailers under certain circumstances. Furthermore, with the increase of live broadcast sales service overflow, the retail prices of both companies will decline, while the live broadcast sales service overflow is more beneficial for consumers. (shrink)