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Background: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability. Objective: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecules as potassium channel modulators have received great scientific attention. Methods: : In this review, we have compiled the literature, patents and patent applications (2011 to 2017) related to different chemical classes of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical classes of selective small molecule have emerged as potassium channel modulators over the past years. Conclusion: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field.

The birth and discovery of electrophysiological science took place in the 18­­th century laying the path for our understanding of nerve membrane ionic currents. The pore-forming proteins, ion channels, are involved and play critical roles in very important physiological and pathological processes, such as neuronal signaling and cardiac excitability, therefore, they serve as therapeutic drug targets. The study of physiological, pharmacological and biophysical properties of ion channels can be done by patch clamp, a gold standard and powerful electrophysiological technique. The current review, in addition to highlight and cover the history of electrophysiology, patch clamp (conventional and automated) technique, and different types of ion channels, will also discuss the importance of ion channels in different neurological diseases and disorders. As the field of neuroscience is growing, this manuscript is intended as a guide to help in understanding the importance of ion channels, particularly in neuroscience, and also in using the patch clamp technique for the study of molecular physiology, pathophysiology, and pharmacology of neuronal ion channels. Importantly, this review will spotlight on the therapeutic aspect of neuronal ion channels. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Locus coeruleus neurons innervate multiple brain regions. These neurons release noradrenaline through their axonal varicosities into the extracellular space through synaptic and volume transmission during states of arousal. The extracellular space is a channel that surrounds brain cells, facilitating diffusion-mediated transport of signaling molecules, ions, and drugs. Distal astrocytic processes expressing β-adrenergic receptors are targets of noradrenaline. In this review, we discuss work in cortical tissue indicating that β-adrenergic agonist, isoproterenol, expands astrocytic processes. Isoproterenol-driven increase in volume of astrocytic processes contributes partially to decrease in the extracellular space volume from 22% to 18%. Decrease in the extracellular space volume suggests increased concentration of ions, neurotransmitters, and neuromodulators diffusing in the extracellular space, which, in turn, facilitates neuronal signaling during noradrenaline release in cortex.

The use of large high-density transducer arrays enables fundamentally new neuroscientific insights through enabling high-throughput monitoring of action potentials of larger neuronal networks (> 1000 neurons) over extended time to see effects of disturbances or developmental effects, and through facilitating detailed investigations of neuronal signaling characteristics at subcellular level, for example, the study of axonal signal propagation that has been largely inaccessible to established methods. Applications include research in neural diseases and pharmacology.

This paper considers neurons as a physical communication medium for intrabody networks of nano/micro-scale machines and formulates a noisy multiobjective optimization problem for a Time Division Multiple Access (TDMA) communication protocol atop the physical layer. The problem is to find the Pareto-optimal TDMA configurations that maximize communication performance (e.g., latency) by multiplexing a given neuronal network to parallelize signal transmissions while maximizing communication robustness (i.e., unlikeliness of signal interference) against noise in neuronal signaling. Using a nonparametric significance test, the proposed stochastic optimizer is designed to statistically determine the superior-inferior relationship between given two solution candidates and seek the optimal trade-offs among communication performance and robustness objectives. Simulation results show that the proposed optimizer efficiently obtains quality TDMA configurations in noisy environments and outperforms existing noise-aware stochastic optimizers.

Recent advances in 2-photon fluorescence lifetime imaging microscopy (2pFLIM) in combination with 2-photon photochemistry have enabled the visualization of neuronal signaling during synaptic plasticity at the level of single dendritic spines in light scattering tissue. Using these techniques, the activity of Ca(2+)/Calmodulin-dependent kinase II (CaMKII) and Ras have been imaged in single spines during synaptic plasticity and associated spine enlargement. These provide two contrasting examples of spatiotemporal regulation of spine signaling: Ras signaling is diffusive and spread over ~10 μm along the dendrites, while CaMKII activation is restricted to the spine undergoing plasticity. In this review, we will discuss the mechanisms and roles of the different spatiotemporal regulation of signaling in neurons, and the impact of the spine structure upon these biochemical signaling processes.

This paper discusses the possibility of quantum coherent oscillations playing a role in neuronal signaling. Consciousness correlates strongly with coherent neural oscillations, however the mechanisms by which neurons synchronize are not fully elucidated. Recent experimental evidence of quantum beats in light-harvesting complexes of plants (LHCII) and bacteria provided a stimulus for seeking similar effects in important structures found in animal cells, especially in neurons. We argue that microtubules (MTs), which play critical roles in all eukaryotic cells, possess structural and functional characteristics that are consistent with quantum coherent excitations in the aromatic groups of their tryptophan residues. Furthermore we outline the consequences of these findings on neuronal processes including the emergence of consciousness.

Adaptation is the ability of a system to respond and reset itself even in the continuing presence of a stimulus. On one hand, adaptation is a physiological necessity that enables proper neuronal signaling and cell movement. On the other hand, adaptation can be a source of annoyance, as it can make biological systems resistant to experimental perturbations. Here we speculate where adaptation might live in eukaryotic chemotaxis and how it can be encoded in the signaling network. We then discuss tools and strategies that can be used to both understand and outwit adaptation in a wide range of cellular contexts. © 2014 Elsevier Inc.

Pheromones are neuronal signals that stimulate conspecific individuals to react to environmental stressors or stimuli. Research on the ascaroside (ascr) pheromones in Caenorhabditis elegans and other nematodes has made great progress since ascr#1 was first isolated and biochemically defined in 2005. In this review, we highlight the current research on the structural diversity, biosynthesis, and pleiotropic neuronal functions of ascr pheromones and their implications in animal physiology. Experimental evidence suggests that ascr biosynthesis starts with conjugation of ascarylose to very long-chain fatty acids that are then processed via peroxisomal β-oxidation to yield diverse ascr pheromones. We also discuss the concentration and stage-dependent pleiotropic neuronal functions of ascr pheromones. These functions include dauer induction, lifespan extension, repulsion, aggregation, mating, foraging and detoxification, among others. These roles are carried out in coordination with three G protein-coupled receptors that function as putative pheromone receptors: SRBC-64/66, SRG-36/37, and DAF-37/38. Pheromone sensing is transmitted in sensory neurons via DAF-16-regulated glutamatergic neurotransmitters. Neuronal peroxisomal fatty acid β-oxidation has important cell-autonomous functions in the regulation of neuroendocrine signaling, including neuroprotection. In the future, translation of our knowledge of nematode ascr pheromones to higher animals might be beneficial, as ascr#1 has some anti-inflammatory effects in mice. To this end, we propose the establishment of pheromics (pheromone omics) as a new subset of integrated disciplinary research area within chemical ecology for system-wide investigation of animal pheromones.

Background. Damage to the plasma membrane is a prevalent but often neglected aspect of traumatic brain injury (TBI), which can impair neuronal signaling and hamper neurological recovery. Objective. This study was performed to assess a new noninvasive intervention to counteract peroxidative damage to the phospholipids in the membrane using the powerful action of foods. Although dietary docosahexaenoic acid (C22:6n-3; DHA) provides protection against TBI, the pervasive effects of TBI that cause phospholipid damage, including to DHA, raises concerns about how to preserve DHA in the brain for optimal functional recovery. Methods. Rats were maintained on curcumin and/or DHA-enriched diets for 2 weeks postinjury, and their brains were subjected to analyses. Results. Fluid percussion injury reduced DHA levels as well as levels of enzymes involved in the metabolism of DHA such as FADS2 and 17β-HSD4 and elevated levels of markers of lipid peroxidation such as 4-hydroxy-2-nonenal (4-HNE) and 4-hydroxy-2-hexenal (4-HHE). These effects were counteracted by DHA or curcumin, whereas the combination of curcumin and DHA had an enhanced effect on DHA and 4-HNE. The combination of curcumin and DHA was also efficient in counteracting reductions in the plasticity markers, brain-derived neurotrophic factor and its receptor p-trkB, and learning ability, which had been lessened after TBI. Conclusions. Curcumin complements the action of DHA on TBI pathology, and this property appears to be a viable strategy to counteract neuronal dysfunction after TBI and complement the application of rehabilitative interventions to foster functional recovery.

There have been a number of advances in our knowledge of neuronal communication in processes involved in development, functioning and disorders of the nervous system. This progress has prompted the Biochemical Society to launch Neuronal Signaling, a new open access journal that aims to expand on the existing knowledge about signaling within and between neurons.

Schizophrenia affects about 1% of the population. It is poorly characterized. A pathway model of disruption offers a good tool to observe network-wide disruptions. Here, we use PathLinker to link hand-curated receptors and transcription factors, and combine the resulting networks into metanetworks. Topologically, schizophrenia pathways were found to not have significantly more node overlap than a random sampling, but were found to have significantly more edge overlap (p = 0.0661, p

We propose a theoretical model consisting of coupled differential equation of membrane potential phase and temperature for describing the neuronal signal in mammals cold receptor. Based on the results from previous work by Roper et al., we modified a nonstochastic phase model for cold receptor neuronal signaling dynamics in mammals. We introduce a new set of temperature adjusted functional parameters which allow saturation characteristic at high and low steady temperatures. The modified model also accommodates the transient neuronal signaling process from high to low temperature by introducing a nonlinear differential equation for the “effective temperature” changes which is coupled to the phase differential equation. This simple model can be considered as a candidate for describing qualitatively the physical mechanism of the corresponding transient process.

Graphene offers promising advantages for biomedical applications. However, adoption of graphene technology in biomedicine also poses important challenges in terms of understanding cell responses, cellular uptake, or the intracellular fate of soluble graphene derivatives. In the biological microenvironment, graphene nanosheets might interact with exposed cellular and subcellular structures, resulting in unexpected regulation of sophisticated biological signaling. More broadly, biomedical devices based on the design of these 2D planar nanostructures for interventions in the central nervous system require an accurate understanding of their interactions with the neuronal milieu. Here, we describe the ability of graphene oxide nanosheets to down-regulate neuronal signaling without affecting cell viability.

Neural-interfaces rely on the ability of electrodes to transduce stimuli into electrical patterns delivered to the brain. In addition to sensitivity to the stimuli, stability in the operating conditions and efficient charge transfer to neurons, the electrodes should not alter the physiological properties of the target tissue. Graphene is emerging as a promising material for neuro-interfacing applications, given its outstanding physico-chemical properties. Here, we use graphene-based substrates (GBSs) to interface neuronal growth. We test our GBSs on brain cell cultures by measuring functional and synaptic integrity of the emerging neuronal networks. We show that GBSs are permissive interfaces, even when uncoated by cell adhesion layers, retaining unaltered neuronal signaling properties, thus being suitable for carbon-based neural prosthetic devices.

Calcium ions generate versatile intracellular signals that control key functions in all types of neurons. Imaging calcium in neurons is particularly important because calcium signals exert their highly specific functions in well-defined cellular subcompartments. In this Primer, we briefly review the general mechanisms of neuronal calcium signaling. We then introduce the calcium imaging devices, including confocal and two-photon microscopy as well as miniaturized devices that are used in freely moving animals. We provide an overview of the classical chemical fluorescent calcium indicators and of the protein-based genetically encoded calcium indicators. Using application examples, we introduce new developments in the field, such as calcium imaging in awake, behaving animals and the use of calcium imaging for mapping single spine sensory inputs in cortical neurons in vivo. We conclude by providing an outlook on the prospects of calcium imaging for the analysis of neuronal signaling and plasticity in various animal models.

The primary cilium is a cellular organelle that is almost ubiquitous in eukaryotes, yet its functions in vertebrates have been slow to emerge. The last fifteen years have been marked by accelerating insight into the biology of primary cilia, arising from the synergy of three major lines of research. These research programs describe a specialized mode of protein trafficking in cilia, reveal that genetic disruptions of primary cilia cause complex human disease syndromes, and establish that Sonic hedgehog (Shh) signal transduction requires the primary cilium. New lines of research have branched off to investigate the role of primary cilia in neuronal signaling, adult neurogenesis, and brain tumor formation. We review a fast expanding literature to determine what we now know about the primary cilium in the developing and adult CNS, and what new directions should lead to further clarity.

The mammalian cryptome consists of bioactive peptides generated by the proteolysis of precursor proteins. It is speculated that the cryptide repertoire increases the complexity of the proteome by an order of magnitude. Cryptides have been found to function in a wide range of processes including neuronal signaling, antigen presentation, and the inflammatory response. Due to their potential as therapeutic agents, there has been an increasing interest in studying cryptides. In this review, we discuss different approaches for discovering these hidden peptides and how proteomic tools can be utilized to aid in their identification and characterization.

Recent findings suggest that spontaneous neurotransmission is a bona fide pathway for interneuronal signaling that operates independent of evoked transmission via distinct presynaptic as well as postsynaptic substrates. This article will examine the role of spontaneous release events in neuronal signaling by focusing on aspects that distinguish this process from evoked neurotransmission, and evaluate the mechanisms that may underlie this segregation. Fil: Kavalali, Ege. UT Southwestern Medical Center; Estados Unidos Fil: Chung, Chi Hye. UT Southwestern Medical Center; Estados Unidos Fil: Khvotchev, Mikhail. UT Southwestern Medical Center; Estados Unidos Fil: Leitz, Jeremy. UT Southwestern Medical Center; Estados Unidos Fil: Nosyreva, Elena. UT Southwestern Medical Center; Estados Unidos Fil: Raingo, Jesica. UT Southwestern Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ramirez, Denise M. O.. UT Southwestern Medical Center; Estados Unidos

Repeated administration of addictive drugs causes cellular and molecular changes believed to be the mechanism of pro-addictive behaviors. Neuroadaptations also take place with repeated administration of amphetamine, methylphenidate and atomoxetine, drugs for Attention Deficit Hyperactivity Disorders (ADHD), and it is speculated that these changes may serve as markers to demonstrate the dependence liability of these therapies. In this review, we enumerate the neuroadaptive changes in molecules associated with neuronal signaling and plasticity, as well as neuronal morphology wrought by repeated administration of ADHD medications. We provide the current perspective on the dependence liability of these therapies, and also suggest of some factors that need to be considered in future investigations, so that what is drawn from animal studies would be better consolidated with those known clinically.

Dendrites and axons typically handle very different aspects of neuronal signaling. However, many of the functional distinctions between these two types of processes are absent in neurons with release-competent dendrites. This raises fundamental questions about the molecular mechanisms that promote and permit functional specialization, and suggests that the 'exceptional' case of presynaptic dendrites may provide important clues on how neuronal polarity is established. To help stimulate thinking on this new front, we summarize some key aspects of the physiology of dendritic neurotransmitter release, together with recent work on the molecular basis of neuronal polarity.

Walter B. Cannon's research on the sympathetic nervous system and neurochemical transmission was pioneering. Wisdom has endowed our body with a powerful autonomic neural regulation of the circulation that provides optimal perfusion of every organ in accordance to its metabolic needs. Exquisite sensors tuned to an optimal internal environment trigger central and peripheral sympathetic and parasympathetic motor neurons and allow desirable and beneficial adjustments to physiologic needs as well as to acute cardiovascular stresses. This short review, presented as The Walter B. Cannon Memorial Award Lecture for 2009, addresses the mechanisms that disrupt sensory signaling and result in a chronic maladjustment of the autonomic neural output that in many cardiovascular diseases results in excessive increases in the risks of dying. The hopes for any reduction of those risks resides in an understanding of the molecular determinants of neuronal signaling.

Gulf War Illness (GWI) is characterized by a wide array of symptomology, which is possibly linked to the prophylactic treatment with pyridostigmine bromide (PB) against neurotoxins. It is now hypothesized that the pathological origin of this multi-symptom illness lies within the central nervous system and is caused by irregular activation of neuronal signaling pathways. To investigate this possibility, a proteomic-based approach was applied to characterize cellular responses of neuronal cells to PB exposure. Protein extracts from cultured neuroblastoma cells treated with 700nM PB for 10 days, as well as extracts from control cells were separated using two-dimensional gel electrophoresis. Twenty two differentially-expressed proteins were identified by MALDI-TOF mass spectrometry (MS). Ingenuity Pathways Analysis (IPA) software was then used to determine the biological functions and canonical pathways associated with the PB-responsive proteins.

Energetics of resting and evoked fMRI signals were related to localized ensemble firing rates (ν) measured by electrophysiology in rats. Two different unstimulated, or baseline, states were established by anesthesia. Halothane and α-chloralose established baseline states of high and low energy, respectively, in which forepaw stimulation excited the contralateral primary somatosensory cortex (S1). With α-chloralose, forepaw stimulation induced strong and reproducible fMRI activations in the contralateral S1, where the ensemble firing was dominated by slow signaling neurons (SSN; ν range of 1–13 Hz). Under halothane, weaker and less reproducible fMRI activations were observed in the contralateral S1 and elsewhere in the cortex, but ensemble activity in S1 was dominated by rapid signaling neurons (RSN; ν range of 13–40 Hz). For both baseline states, the RSN activity (i.e., higher frequencies, including the γ band) did not vary upon stimulation, whereas the SSN activity (i.e., α band and lower frequencies) did change. In the high energy baseline state, a large majority of total oxidative energy [cerebral metabolic rate of oxygen consumption (CMR O2 )] was devoted to RSN activity, whereas in the low energy baseline state, it was roughly divided between SSN and RSN activities. We hypothesize that in the high energy baseline state, the evoked changes in fMRI activation in areas beyond S1 are supported by rich intracortical interactions represented by RSN. We discuss implications for interpreting fMRI data where stimulus-specific ΔCMR O2 is generally small compared with baseline CMR O2 .

Previous research has shown that exposure to HZE particles, which will be encountered on long-term space missions, can adversely affect the ability of rats to perform a variety of behavioral tasks. This outcome has implications for an astronaut’s ability to successfully complete requirements associated with these missions. It has also been found that irradiation can lead to increases in oxidative stress, similar to that seen in the aging brain. Given that astronauts are often middle-aged or older it is important to determine if their age puts them at higher risk for the potentially hazardous effects of exposure to HZE particles. Therefore, we exposed young and old rats to either 1 or 2 Gy of 56 Fe irradiation and evaluated performance in a spatial learning and memory task, in addition to examining levels of dopamine (DA) release from superfused striatal slices. Results indicated that exposure to 56 Fe particles can produce alterations in behavior and neuronal signaling and that these alterations may be more apparent in older organisms, a finding which suggests that the aging brain may be more susceptible to the deleterious effects of irradiation on performance. Therefore, age may be a factor for consideration in planning long-term missions into space.

The sense of hearing is the fastest of our senses and provides the first all-or-none action potential in the auditory nerve in less than four milliseconds. Short stimulus evoked latencies and their minimal variability are hallmarks of auditory processing from spiral ganglia to cortex. Here, we review how even small changes in first spike latencies (FSL) and their variability (jitter) impact auditory temporal processing. We discuss a number of mouse models with degraded FSL/jitter whose mutations occur exclusively in the central auditory system and therefore might serve as candidates to investigate the cellular mechanisms underlying auditory processing disorders (APD).

Gastroparesis (GP), defined as delayed gastric emptying in the absence of any mechanical obstruction, is a challenging clinical condition, mainly because of limited treatment options. Studies in animal models of delayed gastric emptying as well as patients with gastroparesis revealed depletion or ultrastructural changes of interstitial cells of Cajal (ICC) in the gastric tissue, recently termed ICC-opathy. ICC are the pacemakers of the gastrointestinal tract and are involved in the transmission of the neuronal signaling to the smooth muscles. Therefore, lack of ICC could be one explanation of delayed gastric emptying in gastroparetic patients. How frequently ICC changes are observed in gastroparesis is not yet clear. In this review, the data on gastric ICC counts and morphology in animal models and patients with gastroparesis are discussed.

Pain in neonates can induce long-term changes in areas responsible for processing nociceptive stimulus [1]. Astrocytes are active in supporting and controlling neuronal signaling and in response to...

Neuroglial communication in the central nervous system (CNS) is proving to be an important component of neuronal signaling both in normal conditions as well as stressed or injured states. We invest...

Chronic pain, especially headache, is an exceedingly common complication of traumatic brain injury (TBI). In fact, paradoxically, the milder the TBI, the more likely one is to develop headaches. The environment of injury and the associated comorbidities can have a significant impact on the frequency and severity of headaches and commonly serve to direct management of the headaches. Trauma likely contributes to the development of headaches via alterations in neuronal signaling, inflammation, and musculoskeletal changes. The clinical picture of the patient with post-traumatic headaches is often that of a mixed headache disorder with features of tension-type headaches as well as migrainous headaches. Treatment of these headaches is thus often guided by the predominant characteristics of the headaches and can include pharmacologic and nonpharmacologic strategies. Pharmacologic therapies include both abortive and prophylactic agents with prophylaxis targeting comorbidities, primarily impaired sleep. Nonpharmacologic interventions for post-traumatic headaches include thermal and physical modalities as well as cognitive behavioral approaches. As with many postconcussive symptoms, headaches can lessen with time but in up to 25% of patients, chronic headaches are long-term residua.

Ion channels are crucial elements in neuronal signaling and synaptic transmission, and defects in their function are known to underlie rare genetic disorders, including some forms of epilepsy. A second class of channelopathies, characterized by autoantibodies against ligand- and voltage-gated ion channels, cause a variety of defects in peripheral neuromuscular and ganglionic transmission. There is also emerging evidence for autoantibody-mediated mechanisms in subgroups of patients with central nervous system disorders, particularly those involving defects in cognition or sleep and often associated with epilepsy. In all autoimmune channelopathies, the relationship between autoantibody specificity and clinical phenotype is complex. But with this new information, autoimmune channelopathies are detected and treated with increasing success, and future research promises new insights into the mechanisms of dysfunction at neuronal synapses and the determinants of clinical phenotype.

Proteins of the striatin family have been identified in all multicellular animals. They are multidomain molecules containing several protein-interacting motifs. In mammals, these proteins are principally expressed in neurons with a somato-dendritic localization and high concentration in dendritic spines. Recent reports suggest that the proteins of the striatin family are molecular scaffolds that act as links between signal transduction and vesicular trafficking.

Excitation mapping is a method of visualizing the signaling history of neurons with permeant organic cations. It is compatible with high-resolution imaging, allowing concurrent visualization of all neuronal classes and their glutamate-gated excitation histories. Excitation mapping documents the stability and precision of neuronal signaling within a given neuronal class, arguing that single unit electrophysiological sampling accurately reflects neuronal diversity. We here review the theory of excitation mapping, provide methods and protocol links; outline imaging concepts; provide parametric data on the temporal range and physiological sensitivity of excitation mapping; and show that immunocytochemical methods for macromolecules are compatible with excitation mapping.

Ion fluxes through membrane ion channels play crucial roles both in neuronal signaling and the homeostatic control of body electrolytes. Despite our knowledge about the respective ion channels, just how diversification of ion channel genes underlies adaptation of animals to the physical environment remains unknown. Here we systematically survey up to 160 putative ion channel genes in the genome of Ciona intestinalis and compare them with corresponding gene sets from the genomes of the nematode Chaenorhabditis elegans, the fruit fly Drosophila melanogaster, and the more closely related genomes of vertebrates. Ciona has a set of so-called “prototype” genes for ion channels regulating neuronal excitability, or for neurotransmitter receptors, suggesting that genes responsible for neuronal signaling in mammals appear to have diversified mainly via gene duplications of the more restricted members of ancestral genomes before the ascidian/vertebrate divergence. Most genes responsible for modulation of neuronal excitability and pain sensation are absent from the ascidian genome, suggesting that these genes arose after the divergence of urochordates. In contrast, the divergent genes encoding connexins, transient receptor potential-related channels and chloride channels, channels involved rather in homeostatic control, indicate gene duplication events unique to the ascidian lineage. Because several invertebrate-unique channel genes exist in Ciona genome, the crown group of extant vertebrates not only acquired novel channel genes via gene/genome duplications but also discarded some ancient genes that have persisted in invertebrates. Such genome-wide information of ion channel genes in basal chordates enables us to begin correlating the innovation and remodeling of genes with the adaptation of more recent chordates to their physical environment.

Voltage-gated K+channels are important in neuronal signaling, but little is known of their interactions with receptor currents or their behavior during natural stimulation. We used nonparametric and parametric nonlinear modeling of experimental responses, combined with Hodgkin–Huxley style simulation, to examine the roles of K+channels in forming the responses of wild-type (WT) and Shaker mutant ( Sh14) Drosophila photoreceptors to naturalistic stimulus sequences. Naturalistic stimuli gave results different from those of similar experiments with white noise stimuli. Sh14responses were larger and faster than WT. Simulation indicated that, in addition to eliminating the Shaker current, the mutation changed the current flowing through light-dependent channels [light-induced current (LIC)] and increased the delayed rectifier current. Part of the change in LIC could be attributed to direct feedback from the voltage-sensitive ion channels to the light-sensitive channels by the membrane potential. However, we argue that other changes occur in the light detecting machinery of Sh14mutants, possibly during photoreceptor development.

In Drosophila melanogaster food search behaviour, groups of flies swarm around and aggregate on patches of food. We wondered whether flies explore their environment in a cooperative way as interactions between individual flies within a population might influence the flies' ability to locate food sources. We have shown that the food search behavior in the fruit fly Drosophila is a two-step process. Firstly, 'primer' flies search the environment and randomly land on different food patches. Secondly, the remaining group of flies move to the most favorable food source and aggregate there. We call this a 'search-aggregation' cycle. Our data demonstrate that flies do not individually assess all available food resources. Rather, social interactions between flies appear to affect their choice of a specific food patch. A genetic analysis of this 'search-aggregation' behavior shows that flies carrying mutations in specific genes (for example, the dunce (dnc) gene which codes for a phosphodiesterase) were defective in this search-aggregation behavior when compared to normal flies. Future investigations of the neuronal signaling involved in this behavior will help us to understand the complexities of this aspect of Drosophila social behaviour.

Simultaneous, multi-site recording from the brain of freely behaving animals will allow neuroscientists to correlate neuronal activity with external stimulation and behavior. This information is critical for understanding the complex interactions of brain cells. Recent interest in microelectromechanical systems (MEMS) and in particular in bio-MEMS research has led to miniaturization of microelectrodes for extracellular neuronal recording. MEMS technology offers a unique opportunity to build compact, integrated sensors well suited for multi-site recording from freely behaving animals. These devices have the combined capabilities of silicon-integrated circuit processing and thin-film microelectrode sensing. MEMS probes for intracellular recording may offer significantly improved signal quality. Here we discuss the basic concepts that underlie the construction of intracellular MEMS probes. We first review the basics of neuronal signaling and recording, and the principles of microelectrode technology and techniques. Progress in MEMS technology for neuronal recording is then discussed. Finally, we describe MEMS probes for intracellular recording, viz., fabrication of micro-machined silicon needles capable of penetrating cell membranes. Using these needles, we recorded localized extracellular signals from the hawk moth Manduca sexta and obtained first recordings with silicon-based micro-probes from the inside of neurons, using an isolated brain of the sea slug Tritonia diomedea.

Despite their presence throughout the central nervous system, the impact of axonally expressed gamma-amino-butyric acid type-A receptors (GABAARs) on neuronal signaling is just beginning to be understood. A recently published article (Pugh JR and Jahr CE, J Neurosci 31: 565–574, 2011) tackled this important issue by investigating GABAAR-mediated function in axons of cerebellar granule cells. The results of Pugh and Jahr indicate parallel fiber GABAARs enhance neurotransmitter release probability and boost axonal and somatic excitability.

Transient receptor potential (TRP) proteins are a family of ion channels central for sensory signaling. These receptors and, in particular, those involved in thermal sensing are also involved in pain signaling. Noteworthy, thermosensory receptors are polymodal ion channels that respond to both physical and chemical stimuli, thus integrating different environmental clues. In addition, their activity is modulated by algesic agents and lipidergic substances that are primarily released in pathological states. Lipids and lipid-like molecules have been found that can directly activate some thermosensory channels or modulate their activity by either potentiating or inhibiting it. To date, more than 50 endogenous lipids that can regulate TRP channel activity in sensory neurons have been described, thus representing the majority of known endogenous TRP channel modulators. Lipid modulators of TRP channels comprise lipids from a variety of metabolic pathways, including metabolites of the cyclooxygenase, lipoxygenase and cytochrome-P450 pathways, phospholipids and lysophospholipids. Therefore, TRP-channels are able to integrate and interpret incoming signals from the different metabolic lipid pathways. Taken together, the large number of lipids that can activate, sensitize or inhibit neuronal TRP-channels highlights the pivotal role of these molecules in sensory biology as well as in pain transduction and perception. This article is part of a Special Issue entitled: Lipid–protein interactions. Guest Editors: Amitabha Chattopadhyay and Jean-Marie Ruysschaert.

International audience; PDZ (PSD-95/Dlg/ZO-1) domains play a major role in neuronal homeostasis in which they act as scaffold domains regulating cellular trafficking, self-association and catalytic activity of essential proteins such as kinases and phosphatases. Because of their central role in cell signaling, cellular PDZ-containing proteins are preferential targets of viruses to hijack cellular function to their advantage. Here, we describe how the viral G protein of the rabies virus specifically targets the PDZ domain of neuronal enzymes during viral infection. By disrupting the complexes formed by cellular enzymes and their ligands, the virus triggers drastic effect on cell signaling and commitment of the cell to either survival (virulent strains) or death (vaccinal strains). We provide structural and biological evidences that the viral proteins act as competitors endowed with specificity and affinity in an essential cellular process by mimicking PDZ binding motif of cellular partners. Disruption of critical endogenous protein-protein interactions by viral protein drastically alters intracellular protein trafficking and catalytic activity of cellular proteins that control cell homeostasis. This work opens up many perspectives to mimic viral sequences and developing innovative therapies to manipulate cellular homeostasis.