Excitability Of Nerve Cells Research Articles

Analysis of nerve excitability in the dentate gyrus of the hippocampus in cerebral ischaemia-reperfusion mice

Ischemic stroke often leads to cognitive dysfunction, which delays the recovery process of patients. However, its pathogenesis is not yet clear. In this study, the cerebral ischemia-reperfusion model was built as the experimental object, and the hippocampal dentate gyrus (DG) was the target brain area. TTC staining was used to evaluate the degree of cerebral infarction, and nerve cell membrane potentials and local field potentials (LFPs) signals were collected to explore the mechanism of cognitive impairment in ischemia-reperfusion mice. The results showed that the infarcted area on the right side of the brain of the mice in the model group was white. The resting membrane potential, the number of action potential discharges, the post-hyperpolarization potential and the maximum ascending slope of the hippocampal DG nerve cells in the model mice were significantly lower than those in the control group ( P < 0.01); the peak time, half-wave width, threshold and maximum descending slope of the action potential were significantly higher than those in the control group ( P < 0.01). The time-frequency energy values of LFPs signals in the θ and γ bands of mice in the ischemia and reperfusion groups were significantly reduced ( P < 0.01), and the time-frequency energy values in the reperfusion group were increased compared with the ischemia group ( P < 0.01). The signal complexity of LFPs in the ischemia and reperfusion group was significantly reduced ( P < 0.05), and the signal complexity in the reperfusion group was increased compared with the ischemia group ( P < 0.05). In summary, cerebral ischemia-reperfusion reduced the excitability of nerve cells in the DG area of the mouse hippocampus; cerebral ischemia reduced the discharge activity and signal complexity of nerve cells, and the electrophysiological indicators recovered after reperfusion, but it failed to reach the healthy state during the experiment period.

Thermodynamic model for memory

A thermodynamic model for memory formation is proposed. Key points include: 1) Any thought or consciousness corresponds to a thermodynamic system of nerve cells. 2) The system concept of nerve cells can only be described by thermodynamics of condensed matter. 3) The memory structure is logically associated with the system structure or the normal structure of biology. 4) The development of our thoughts is processed irreversibly, and numerous states or thoughts can be generated. 5) Memory formation results from the reorganization and change of cellular structures (or memory structures), which are related to nerve cell skeleton and membrane. Their alteration can change the excitability of nerve cells and the pathway of neural impulse conduction. 6) Amnesia results from the loss of thermodynamic stability of the memory structure, which can be achieved by different ways. Some related phenomena and facts are discussed. The analysis shows that thermodynamics can account for the basic properties of memory.

Current state of research on acupuncture for the treatment of post-stroke dysphagia: a scoping review.

Post-stroke dysphagia (PSD) is a common complication of stroke. Acupuncture as one of the traditional therapies in traditional Chinese medicine (TCM), can change the excitability of cerebral cortical nerve cells, and promote the recovery of neurological and swallowing functions. Several clinical primary studies (including RCTs, cohort studies, etc.) and systematic reviews have demonstrated its efficacy and safety in patients with PSD. The positive effects of acupuncture on PSD are also mentioned in international clinical and treatment guidelines, while there is no synthesis of this evidence. This scoping review aims to summarize the evidence from clinical primary studies, reviews, systematic reviews, and guidelines on acupuncture for the treatment of PSD and explore the breadth of this evidence, provide an overview of the range and characteristics of existing evidence, research gaps, and future research priorities in treating PSD with acupuncture. PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wan Fang Data, and VIP databases were searched from inception until June 12, 2024. The relevant data were presented through bubble diagrams, line graphs, and structured tables along with descriptive statistics and analysis. This scoping review was conducted based on the PRISMA-ScR Checklist. A total of 1,130 studies were included. Most of the studies were conducted in China, with the number increasing over time. The studies included 254 reviews, 815 clinical studies (678 RCTs,107 nRCTs, 12 case reports, 14 cohort studies, and four case series), 51 systematic reviews, and 10 guidelines. Acupuncture interventions included manual acupuncture (MA), electroacupuncture (EA), and MA/EA combined with acupuncture-related methods (such as scalp acupuncture, auricular acupuncture, warm acupuncture, etc.). The most frequently used acupoint was RN23. Acupuncture is often applied in combination with other treatments, such as herbal medicine, Western medicine, rehabilitation training, swallowing training, or catheter balloon dilatation. Effective rates and WTS were the most frequently used outcomes. Most studies reported significant efficacy and only a few studies explicitly reported adverse events. Acupuncture received positive recommendations in nine guidelines for the treatment of PSD. As a convenient and safe traditional Chinese medicine therapy with its characteristics, acupuncture can improve different stages and types of dysphagia without causing serious adverse reactions. In the future, more standardized international cooperative clinical research is needed to identify the influence of different acupuncture intervention times on the curative effect and dose-effect relationship of acupuncture; standardize the clinical acupoint selection scheme of acupuncture; develop a COS with TCM characteristics to improve the quality of outcome reporting, This will enable different research data to be summarized and compared, reduce resource waste, and provide more high-quality evidence.

Tongue acupuncture for the treatment of post-stroke dysphagia: a meta-analysis of randomized controlled trials.

Post-stroke dysphagia is the most common neurological impairment after stroke. The swallowing process is controlled by a network made up of the cerebral cortex, subcortical area, and brainstem structure. The disruption of the swallowing network after stroke leads to dysphagia. The affected swallowing muscles after stroke mainly include the laryngeal muscles (suprahyoid muscle and thyrohyoid muscle) and infrahyoid muscle. These muscles experience kinematic effects and muscle strength weakens, resulting in reduced movement in the swallowing process. Acupuncture can change the excitability of cerebral cortical nerve cells, promote the recovery of neurological function, and enhance neuromuscular excitability, ultimately improving the control of swallowing-related nerves and muscles and promoting swallowing functional recovery. In this meta-analysis, we systematically evaluate the clinical efficacy of acupuncture in the treatment of post-stroke dysphagia. Randomized controlled trials of tongue acupuncture therapy for post-stroke dysphagia were searched and selected from seven electronic databases (PubMed, CBM, Cochrane, Embase, CNKI, VPCS, and Wan fang). The Cochrane Collaboration tool was used to conduct methodological quality assessment. Rev. Man 5.4 software was utilized to perform data analysis. A total of 15 studies with 1,094 patients were included. Meta-analysis Showed that WST score WST score (MD = -0.56, 95% CI (-1.23, 0.12), Z = 1.62, p < 0.00001), SSA score (MD = -1.65, 95% CI (-2.02, -1.28), Z = 8.77, p < 0.00001). These results suggested that the treatment group (tongue acupuncture or tongue acupuncture combined with other therapies) was superior to the control group in reducing WST scores and SSA scores. The clinical efficacy of the tongue acupuncture group was better compared with the control group (MD = 3.83, 95% CI (2.61, 5.62), Z = 6.88, p < 0.00001). The meta-analysis showed that the total effective rate of patients with dysphagia after stroke in the treatment group (acupuncture, tongue acupuncture, and acupuncture combined with other therapy) was higher than that in the control group. These results indicated that acupuncture, tongue acupuncture, and acupuncture combined with other therapy can improve post-stroke dysphagia.

Potassium channel openers targeting different sites of the channel.

Voltage-gated ion channels play essential roles in generating and shaping the electrical excitability of nerve and heart cells. Mutations in these ion channels can cause diseases, which can be treated with pharmaceuticals targeting specific ion channels. While many pharmaceuticals cause their effects by blocking the ion-conducting pore to prevent the ion current, only a few exert their therapeutic effect by opening (or activating) the channel. While they see limited use as pharmaceuticals at present, recent research has identified many different types of compounds that can open ion channels. Here, I will present data from three classes of compounds capable of opening voltage-gated potassium (Kv) channels. (1) The first class includes resin acids and polyunsaturated fatty acids. These negatively charged compounds have close interactions with the channel's positively charged voltage sensor, opening the channel by pulling the sensor to an activated position. This interaction occurs at the interface between the phospholipid bilayer and the channel protein. (2) Biaryl sulfonamide acids can access the voltage sensor through the extracellular space, allowing them to activate the Kv1-like Shaker channel. (3) Warfarine-like tautomers activate Kv1.5 channels via close interactions with the linker connecting the voltage sensor and the channel's ion conducting pore domain. Characterizing different binding sites and compounds that use them on different ion channels will hopefully lead to better treatments for diseases caused by altered excitability.

Antiarrhythmic calcium channel blocker verapamil inhibits trek currents in sympathetic neurons.

Background and Purpose: Verapamil, a drug widely used in certain cardiac pathologies, exert its therapeutic effect mainly through the blockade of cardiac L-type calcium channels. However, we also know that both voltage-dependent and certain potassium channels are blocked by verapamil. Because sympathetic neurons of the superior cervical ganglion (SCG) are known to express a good variety of potassium currents, and to finely tune cardiac activity, we speculated that the effect of verapamil on these SCG potassium channels could explain part of the therapeutic action of this drug. To address this question, we decided to study, the effects of verapamil on three different potassium currents observed in SCG neurons: delayed rectifier, A-type and TREK (a subfamily of K2P channels) currents. We also investigated the effect of verapamil on the electrical behavior of sympathetic SCG neurons. Experimental Approach: We employed the Patch-Clamp technique to mouse SCG neurons in culture. Key Results: We found that verapamil depolarizes of the resting membrane potential of SCG neurons. Moreover, we demonstrated that this drug also inhibits A-type potassium currents. Finally, and most importantly, we revealed that the current driven through TREK channels is also inhibited in the presence of verapamil. Conclusion and Implications: We have shown that verapamil causes a clear alteration of excitability in sympathetic nerve cells. This fact undoubtedly leads to an alteration of the sympathetic-parasympathetic balance which may affect cardiac function. Therefore, we propose that these possible peripheral alterations in the autonomic system should be taken into consideration in the prescription of this drug.

THE VALUES AND THE DIFFERENCES OF THE SEROTONIN LEVELS IN SERUM AND BRAIN TISSUE IN AN INDUCED DIABETIC NEPHROPATHY WHITE LABORATORY RAT UNDER THE IMPACT OF PERINDOPRIL AND CANDESARTAN

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays a role in the pathophysiology of hypertension, heart failure, renal failure and other cardiovascular disorders. RAAS is activated in diabetic nephropathy (DN) and leads to more renal damage. Angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers suppress this (ARBs). A large body of evidence demonstrates that, in addition to its typical activity as a hormone, Ang II is a neuropeptide produced by the central nervous system (CNS) that acts as a regulator of neurotransmission and nerve cell excitability. Peripheral serotonin is an endocrine component that promotes energy storage efficiency. Serotonin also enters the bloodstream and interacts with multiple organs, priming the body for energy storage by promoting insulin secretion and de novo lipogenesis in the liver and white adipose tissue. However, the actions of serotonin extend beyond neuronal communication in the CNS and enteric nervous system (ENS) to peripheral tissues. Serotonin mediates numerous nonneuronal processes such as bladder function, respiratory drive, hemostasis, vascular tone, immune function, and intestinal inflammation . The goal of this study is to see how the ACE inhibitor perindopril and the ARB AT1 candesartan, taken singly and in combination (double blockade), affect serotonin levels in the serum and brain tissue of Wistar rats with DN caused by streptozotocin (STZ). The levels of serotonin in the serum and brain of four experimental groups of animals were measured using an enzyme-linked immunosorbent assay (ELISA): a control group with DN, a group with DN treated with perindopril, a group with DN treated with candesartan, and a DN group treated with a combination of perindopril and candesartan. Perindopril (6 mg/Kg/day), candesartan (5 mg/Kg/day), and dual therapy with perindopril (3 mg/Kg/day) and candesartan (2,5 mg/Kg/day) were given orally every day for eight weeks, beginning four weeks after STZ was given, whereas the control group received just water. The rats were slaughtered at the end of the therapy so that the serum and brain tissue could be used to test serotonin levels. The results showed that blocking the renin-angiotensin system (RAS) with perindopril, candesartan, or their combination considerably decreased serotonin levels in the serum but dramatically elevated serotonin levels in the brain tissue in all groups.

Пошук цілей терапії, що змінює перебіг хвороби Паркінсона

Актуальність. Хвороба Паркінсона (ХП) — це багатосистемне захворювання, що вимагає більш комплексного підходу до свого вивчення й лікування. Мета дослідження: дати клініко-лабораторну характеристику пацієнтів із ХП, у яких розвиток рухових симптомів пов’язаний із дією провокуючих чинників, і навести теоретичне обґрунтування електрофізіологічних явищ, що лежать в основі захворювання і/або асоціюються з ним. Матеріали та методи. Було обстежено 207 пацієнтів із ХП. Проведені анкетний аналіз, лабораторні дослідження. Результати. Серед пацієнтів із швидко прогресуючим типом ХП біль при обстеженні відзначений у 49 (42,2 %) випадках, стрес — у 73 (62,3 %). При повільно прогресуючому перебігу больові синдроми зареєстрованi в 14 (15,4 %) випадках, стресові — у 53 (58,2 %) випадках. Відзначено статистично значущі відмінності між пацієнтами зі швидко й повільно прогресуючим перебігом ХП за кількістю випадків герпетичних захворювань, запальних захворювань порожнини рота. Результати лабораторних тестів також показали статистично значущі відмінності між цими групами за рівнем IL-1β і кортизолу в сироватці крові, рівнем IL-1β в спинномозковій рідині й коефіцієнтом альбуміну. Виявлено більшу кількість провокуючих чинників розвитку ХП у пацієнтів зі швидко прогресуючим перебігом захворювання. У пацієнтів зі швидко прогресуючою ХП була виявлена кореляція між кількістю провокуючих чинників і рівнем антитіл до α-синуклеїну (r = –0,18), IL-10 (r = 0,31) і кортизолу (r = 0,18) у сироватці крові. Деякі об’єктивні характеристики нерухових симптомів ХП статистично значущо корелювали з рівнем лабораторних показників у сироватці крові (значення MOCA з рівнем кортизолу (r = –0,4); значення PSQI з антитілами до α-синуклеїну (r = 0,31); значення ESS з рівнем IL-10 (r = –0,21)). Значні гострі психологічні стреси й больові синдроми можуть змінювати характер поширення хвиль деполяризації в нервовій системі з утворенням «автохвильової півтіні». Наведені можливі клінічні критерії ефективності терапії, що змінює перебіг ХП. Висновки. Больові синдроми й гострі значні психологічні стреси призводять не тільки до виникнення рухових симптомів ХП, а й до швидкого прогресування захворювання. Дія провокуючих чинників може проявлятися не тільки клінічними, морфологічними й лабораторними змінами, а й змінами збудливості нервових клітин. Електрофізіологічна (автохвильова) півтінь може розглядатися як імовірна мішень для дії терапії, що змінює перебіг ХП.

Single Amino Acid Changes in the Ryanodine Receptor in the Human Population Have Effects In Vivo on Caenorhabditis elegans Neuro-Muscular Function.

The ryanodine receptor mediates intracellular calcium ion release with excitation of nerve and muscle cells. Ryanodine receptor missense variants cause a number of myopathologies, such as malignant hyperthermia, and have been linked with various neuropathologies, including Alzheimer’s disease. We characterized the consequences of ryanodine receptor variants in vivo. Eight Caenorhabditis elegans strains, with ryanodine receptor modifications equivalent to human myopathic RYR1 variants, were generated by genome editing. In humans, these variants are rare and confer sensitivity to the inhalational anaesthetic halothane when heterozygous. Increased sensitivity to halothane was found in both homozygous and heterozygous C. elegans. Close analysis revealed distinct subtle locomotion defects, due to the different single amino acid residue changes, even in the absence of the external triggering agent. Distinct pre- and postsynaptic consequences of the variants were characterized through the responses to cholinergic pharmacological agents. The range of phenotypes reflects the complexity of the regulatory inputs to the ryanodine receptor and the criticality of the calcium ion channel opening properties, in different cell types and with age. Ryanodine receptors with these single amino acid residue changes still function as calcium ion channels, but with altered properties which are likely to have subtle consequences for human carriers of such variants. The long-term consequences of subtly altered calcium ion signalling could be cumulative and may be focussed in the smaller nerve cells rather than the more robust muscle cells. It was important to assess phenotypes in vivo to properly appreciate consequences for a whole organism.

Cellular Response to ELF-MF and Heat: Evidence for a Common Involvement of Heat Shock Proteins?

It has been shown that magnetic fields in the extremely low frequency range (ELF-MF) can act as a stressor in various in vivo or in vitro systems, at flux density levels below those inducing excitation of nerve and muscle cells, which are setting the limits used by most generally accepted exposure guidelines, such as the ones published by the International Commission on Non-Ionizing Radiation Protection. In response to a variety of physiological and environmental factors, including heat, cells activate an ancient signaling pathway leading to the transient expression of heat shock proteins (HSPs), which exhibit sophisticated protection mechanisms. A number of studies suggest that also ELF-MF exposure can activate the cellular stress response and cause increased HSPs expression, both on the mRNA and the protein levels. In this review, we provide some of the presently available data on cellular responses, especially regarding HSP expression, due to single and combined exposure to ELF-MF and heat, with the aim to compare the induced effects and to detect possible common modes of action. Some evidence suggest that MF and heat can act as costressors inducing a kind of thermotolerance in cell cultures and in organisms. The MF exposure might produce a potentiated or synergistic biological response such as an increase in HSPs expression, in combination with a well-defined stress, and in turn exert beneficial effects during certain circumstances.

A Cav3.2/Stac1 molecular complex controls T-type channel expression at the plasma membrane

ABSTRACTLow-voltage-activated T-type calcium channels are essential contributors to neuronal physiology where they play complex yet fundamentally important roles in shaping intrinsic excitability of nerve cells and neurotransmission. Aberrant neuronal excitability caused by alteration of T-type channel expression has been linked to a number of neuronal disorders including epilepsy, sleep disturbance, autism, and painful chronic neuropathy. Hence, there is increased interest in identifying the cellular mechanisms and actors that underlie the trafficking of T-type channels in normal and pathological conditions. In the present study, we assessed the ability of Stac adaptor proteins to associate with and modulate surface expression of T-type channels. We report the existence of a Cav3.2/Stac1 molecular complex that relies on the binding of Stac1 to the amino-terminal region of the channel. This interaction potently modulates expression of the channel protein at the cell surface resulting in an increased T-type conductance. Altogether, our data establish Stac1 as an important modulator of T-type channel expression and provide new insights into the molecular mechanisms underlying the trafficking of T-type channels to the plasma membrane.

PHYSIOLOGICAL PROPERTIE S OF CO2 AS SUBSTANTIATION OF ORIINALITY OF CARBOXYTHERAPY

CO2 due to the optimal mechanism of maintaining of its reserve is a universal condition for the existence of thebody. A physiological concentration of CO2 in the cells is an absolutely necessary condition for normal course ofbiochemical processes. CO2 is a natural regulator of respiration, blood circulation, metabolism, electrolyte balance,acid-base balance, the excitability of nerve cells, smooth muscle tone. Physiological properties provide CO2 diverselocal and resorptive effects, due to this carboxytherapy has become an effective and safe method of treatment inmany areas of medicine.

Kinetics by X-Ray Crystallography: Sequential Substitution of K+ Bound To Na+, K+-ATPase

Na+, K+-ATPase is one of the most important members of the P-type ATPase family. It transports 3 Na+ from the cytoplasm into the extracellular medium and countertransports 2 K+ per ATP hydrolyzed in each reaction cycle, thereby establishing gradients for Na+ and K+ across the membrane. These ion gradients are used in many fundamental processes, notably, excitation of nerve cells. Na+, K+-ATPase is also regarded as a membrane receptor for cardiotonic steroids, such as ouabain and digoxin, which have been prescribed for treatment of heart failure for ∼200 years. Crystallographic studies of Ca2+-ATPase of sarcoplasmic reticulum have provided detailed information on the gating mechanism on the cytoplasmic side, but little on the gating on the other side. This is partly because H+ countertransported by Ca2+-ATPase is invisible to X-rays. In this regard, Na+, K+-ATPase has a fundamental advantage over Ca2+-ATPase, as it countertransports K+ and even its congeners of larger atomic numbers. Here, we carried out X-ray crystallography and isotopic measurements of the ATPase in a state analogous to E2·Pi·2K+ to visualize the substitution process of 2 bound K+ with congeners in the extracellular medium. Crystals were soaked in a buffer containing K+ congeners and anomalous diffraction data were collected. The electron density maps at various incubation times clearly show that the substitution of the 2 K+ with congeners occurs substantially faster at site II. An analysis of B-factors of protein atoms in the crystal shows that the M3-M4E helix pair opens and closes the ion pathway leading to the extracellular medium. These results indicate that site I K+ is the first cation to bind to the empty cation binding sites after releasing 3 Na+.

X-Ray Crystallographic Study of Na,K-ATPase in Complex with Cardiotonic Steroids

Na,K-ATPase transports three sodium ions from the cytoplasm to the extracellular side and counter-transports two potassium ions upon hydrolysis of one ATP in each reaction cycle, thereby establishing gradients for sodium and potassium ions across the membrane. These ion gradients are used in many fundamental processes, notably, excitation of nerve cells. It is one of the most important members of the P-type ATPases. It is a hetero-trimer complex, consisting of alpha-subunit (112K), beta-subunit (55K) and FXYD regulatory protein (10K). Na,K-ATPase is also regarded as a membrane receptor for cardiotonic steroids (CTS), including digoxin prescribed for congestive heart failure and supraventricular arrhythmias for ∼200 years. Moreover, CTS have been studied as potential drugs for cancer chemotherapy, because they inhibit growth of cancer cells through the binding to Na,K-ATPase. Thus, the elucidation of the binding mechanism of CTS to Na,K-ATPase has direct medical implication. We reported a crystal structure with bound ouabain at 2.8 A resolution (Ogawa et al., PNAS 2009), but the affinity of ouabain under the conditions employed is low due to antagonism with bound potassium. As to the high affinity ouabain-bound form, a crystal structure was reported very recently by other group, but at only 3.4 A resolution with a very low completeness (Laursen et al., PNAS 2013). Thus, higher-resolution structures are still awaited. Moreover, structures bound with other CTSs having different sugar moieties and/or different lactone rings are also awaited. Here, we report our recent crystal structures with bound several CTSs, including different sugar moieties and lactone rings, at better than 3.0 A resolution. These structures provide detailed information on the interaction of Na,K-ATPase and CTS and may lead us to design better drugs for treating heart failure, arrhythmias and cancer.

Adapting to a changing environment: non-obvious thresholds in multi-scale systems.

Many natural and technological systems fail to adapt to changing external conditions and move to a different state if the conditions vary too fast. Such 'non-adiabatic' processes are ubiquitous, but little understood. We identify these processes with a new nonlinear phenomenon-an intricate threshold where a forced system fails to adiabatically follow a changing stable state. In systems with multiple time scales, we derive existence conditions that show such thresholds to be generic, but non-obvious, meaning they cannot be captured by traditional stability theory. Rather, the phenomenon can be analysed using concepts from modern singular perturbation theory: folded singularities and canard trajectories, including composite canards. Thus, non-obvious thresholds should explain the failure to adapt to a changing environment in a wide range of multi-scale systems including: tipping points in the climate system, regime shifts in ecosystems, excitability in nerve cells, adaptation failure in regulatory genes and adiabatic switching in technology.

Transmembrane calcium current: Mechanism, registration procedures, calcium-mediated modulators of synaptic transmission

The paper reviews data on mechanisms of calcium current and methods of its recording. The involvement of calcium ions in excitation of nerve and muscle cells and in particular in synaptic transmission processes is considered. Calcium signaling relies on voltage-dependent and ligand-gated calcium channels. The review focuses mainly on calcium currents flowing through voltage-dependent channels. The conditions evoking calcium currents, basic methods of their recordings, as well as effects of some important endogenous modulators of neuromuscular transmission are overviewed.

Sialic Acids in the Brain: Gangliosides and Polysialic Acid in Nervous System Development, Stability, Disease, and Regeneration

Every cell in nature carries a rich surface coat of glycans, its glycocalyx, which constitutes the cell's interface with its environment. In eukaryotes, the glycocalyx is composed of glycolipids, glycoproteins, and proteoglycans, the compositions of which vary among different tissues and cell types. Many of the linear and branched glycans on cell surface glycoproteins and glycolipids of vertebrates are terminated with sialic acids, nine-carbon sugars with a carboxylic acid, a glycerol side-chain, and an N-acyl group that, along with their display at the outmost end of cell surface glycans, provide for varied molecular interactions. Among their functions, sialic acids regulate cell-cell interactions, modulate the activities of their glycoprotein and glycolipid scaffolds as well as other cell surface molecules, and are receptors for pathogens and toxins. In the brain, two families of sialoglycans are of particular interest: gangliosides and polysialic acid. Gangliosides, sialylated glycosphingolipids, are the most abundant sialoglycans of nerve cells. Mouse genetic studies and human disorders of ganglioside metabolism implicate gangliosides in axon-myelin interactions, axon stability, axon regeneration, and the modulation of nerve cell excitability. Polysialic acid is a unique homopolymer that reaches >90 sialic acid residues attached to select glycoproteins, especially the neural cell adhesion molecule in the brain. Molecular, cellular, and genetic studies implicate polysialic acid in the control of cell-cell and cell-matrix interactions, intermolecular interactions at cell surfaces, and interactions with other molecules in the cellular environment. Polysialic acid is essential for appropriate brain development, and polymorphisms in the human genes responsible for polysialic acid biosynthesis are associated with psychiatric disorders including schizophrenia, autism, and bipolar disorder. Polysialic acid also appears to play a role in adult brain plasticity, including regeneration. Together, vertebrate brain sialoglycans are key regulatory components that contribute to proper development, maintenance, and health of the nervous system.

The Activation Dynamics of Class C Gpcrs Revealed by Single Molecule FRET

G-protein-coupled receptors (GPCRs) are the largest and most diverse family of membrane signaling proteins. Binding of an extracellular signal to a GPCR activates G protein, which in turn modulates the activity of different downstream cellular effectors. Recent biochemical, pharmacological and biophysical studies suggest that GPCRs do not simply act as on-off switches but instead exist in multiple conformational and functional states where they may signal to distinct G proteins and other partners. However, despite recent advances, many aspects of signal transduction through GPCRs is still not well understood. Here we report a novel functional assay based on single molecule FRET to probe real-time conformational dynamics of isolated receptors. Using our assay, we studied metabotropic glutamate receptors (mGluRs), dimeric members of class C GPCR family, which are involved in modulation of synaptic transmission and excitability of nerve cells. Experiments on mGluR2 and mGluR3 homodimers reveal multiple stable conformational states. Strikingly, in spite of more than 70% sequence identity between mGluR2 and mGluR3, we observe substantial differences in their inherent dynamics and basal activity in absence of ligand. Our approach should make it possible to directly quantify how drugs stabilize conformational states of receptors and provide new insights into the molecular mechanisms of GPCR signaling.

4-aminopyridine improves lower urinary tract symptoms in a patient with benign prostatic hyperplasia and downbeat nystagmus syndrome.

Aminopyridines are potassium channel blockers that increase the excitability of nerve cells and axons; therefore, they are widely used to treat different neurological disorders. Here we present a patient with idiopathic downbeat nystagmus and lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia who was treated with the sustained-release form of 4-aminopyridine (4-AP). During treatment with 4-AP, the LUTS improved. This improvement was monitored by using uroflowmetry and the International Prostate Symptom Score. A significant improvement of symptoms was observed in relation to the voided volume. This included an improved emptying of the bladder without an increase in residual urine. In animal studies, both nonselective K+ channel blockade and selective voltage-sensitive potassium blockade by 4-AP resulted in increased contraction on rat detrusor strips. To our knowledge, this is the first clinical observation of the mode of action of 4-AP in urological symptoms in humans.

The Protein-Protein Interaction Networks of Dendritic Spines in the Early Phase of Long-Term Potentiation

The neuron is a basic element of brain networks. Changes of nerve cell excitability, the conduction of excitation, synaptic memory-forming in the case of the temporal coincidence of synaptic events are the obvious functions of the neuron - element of brain networks. The implementation of the neuron function depends on actions of its numerous molecular systems. The generalization of the complex processes of emergence of synaptic memory, that occur even in separate neuronal compartments, without special tools is a difficult, if at all possible, task. A technology that combines the creation of databases (elements and their relationships) with a visual representation in the form of networks facilitates this process. The developed protein-protein interaction network in dendritic spines of hippocampal pyramidal neurons facilitates the synthesis of numerous experimental data in conceptual knowledge about the principles and molecular mechanisms of neurons functioning.