Depolarization Of Fibers Research Articles

Maximizing the translational potential of neurophysiology in amyotrophic lateral sclerosis: a study on compound muscle action potentials

Mouse models of amyotrophic lateral sclerosis (ALS) enable testing of novel therapeutic interventions. However, treatments that have extended survival in mice have often failed to translate into human benefit in clinical trials. Compound muscle action potentials (CMAPs) are a simple neurophysiological test that measures the summation of muscle fiber depolarization in response to maximal stimulation of the innervating nerve. CMAPs can be measured in both mice and humans and decline with motor axon loss in ALS, making them a potential translational read-out of disease progression. We assessed the translational potential of CMAPs and ascertained time points when human and mouse data aligned most closely. We extracted data from 18 human studies and compared with results generated from SOD1G93A and control mice at different ages across different muscles. The relative CMAP amplitude difference between SOD1G93A and control mice in tibialis anterior (TA) and gastrocnemius muscles at 70 days of age was most similar to the relative difference between baseline ALS patient CMAP measurements and healthy controls in the abductor pollicis brevis (APB) muscle. We also found that the relative decline in SOD1G93A TA CMAP amplitude between 70 and 140 days was similar to that observed in 12 month human longitudinal studies in APB. Our findings suggest CMAP amplitudes can provide a “translational window”, from which to make comparisons between the SOD1G93A model and human ALS patients. CMAPs are easy to perform and can help determine the most clinically relevant starting/end points for preclinical studies and provide a basis for predicting potential clinical effect sizes.

Distinguishing reflex from non-reflex responses elicited by transcutaneous spinal stimulation targeting the lumbosacral cord in healthy individuals

Transcutaneous spinal stimulation (TSS) studies rely on the depolarization of afferent fibers to provide input to the spinal cord; however, this has not been routinely ascertained. Thus, we aimed to characterize the types of responses evoked by TSS and establish paired-pulse ratio cutoffs that distinguish posterior root reflexes, evoked by stimulation of afferent nerve fibers, from motor responses, evoked by stimulation of efferent nerve fibers. Twelve neurologically intact participants (six women) underwent unipolar TSS (cathode over T11-12 spinal processes, anode paraumbilically) while resting supine. In six participants, unipolar TSS was repeated 2–3 months later and also compared to a bipolar TSS configuration (cathode 2.5 cm below T11-12, anode 5 cm above cathode). EMG signals were recorded from 16 leg muscles. A paired-pulse paradigm was applied at interstimulus intervals (ISIs) of 25, 50, 100, 200, and 400 ms. Responses were categorized by three assessors into reflexes, motor responses, or their combination (mixed responses) based on the visual presence/absence of paired-pulse suppression across ISIs. The paired-pulse ratio that best discriminated between response types was derived for each ISI. These cutoffs were validated by repeating unipolar TSS 2–3 months later and with bipolar TSS. Unipolar TSS evoked only reflexes (90%) and mixed responses (10%), which were mainly recorded in the quadriceps muscles (25–42%). Paired-pulse ratios of 0.51 (25-ms ISI) and 0.47 (50-ms ISI) best distinguished reflexes from mixed responses (100% sensitivity, > 99.2% specificity). These cutoffs performed well in the repeated unipolar TSS session (100% sensitivity, > 89% specificity). Bipolar TSS exclusively elicited reflexes which were all correctly classified. These results can be utilized in future studies to ensure that the input to the spinal cord originates from the depolarization of large afferents. This knowledge can be applied to improve the design of future neurophysiological studies and increase the fidelity of neuromodulation interventions.

Effects and mechanisms of acupuncture analgesia mediated by afferent nerves in acupoint microenvironments.

In the past few decades, the use of acupuncture analgesia in clinical practice has increased worldwide. This is due to its various benefits, including natural alleviation of pain without causing various adverse effects associated with non-steroidal anti-inflammatory drugs (NSAID) and opioids. The acupoint represents the initial site of acupuncture stimulation, where diverse types of nerve fibers located at the acupoint hold significant roles in the generation and transmission of acupuncture-related information. In this study, we analyzed the patterns and mechanisms of acupuncture analgesic mediated by acupoint afferent fibers, and found that acupuncture stimulates acupoints which rapidly and directly induces activation of high-density primary afferent fibers under the acupoints, including myelinated A fibers and unmyelinated C fibers. During acupuncture stimulation at the muscle layer, the analgesic effects can be induced by stimulation of A fiber threshold intensity. At the skin layer, the analgesic effects can only be produced by stimulation of C fiber threshold intensity. Electroacupuncture (EA) activates A fibers, while manual acupuncture (MA) activates both A and C fibers. Furthermore, acupuncture alters acupoint microenvironments, which positively modulates afferent fibers, enhancing the transmission of analgesic signals. In addition to local activation and conduction at acupoints, nerve fibers mediate the transmission of acupuncture information to pain centers. In the spinal cord, acupuncture activates neurons by inducing afferent fiber depolarization, modulating pain gating, inhibiting long-term potentiation (LTP) of the spinal dorsal horn and wide dynamic range (WDR) neuronal activities. At higher nerve centers, acupuncture inhibits neuronal activation in pain-related brain regions. In summary, acupuncture inhibits pain signal transmission at peripheral and central systems by activating different patterns of afferent fibers located on various layers of acupoints. This study provides ideas for enhancing the precise application and clinical translation of acupuncture.

Constitutive Expression of Hif2α Confers Acute O2 Sensitivity to Carotid Body Glomus Cells.

Acute oxygen (O2) sensing and adaptation to hypoxia are essential for physiological homeostasis. The prototypical acute O2 sensing organ is the carotid body, which contains chemosensory glomus cells expressing O2-sensitive K+ channels. Inhibition of these channels during hypoxia leads to cell depolarization, transmitter release, and activation of afferent sensory fibers terminating in the brain stem respiratory and autonomic centers. Focusing on recent data, here we discuss the special sensitivity of glomus cell mitochondria to changes in O2 tension due to Hif2α-dependent expression of several atypical mitochondrial electron transport chain subunits and enzymes. These are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O2 availability. We report that ablation of Epas1 (the gene coding Hif2α) causes a selective downregulation of the atypical mitochondrial genes and a strong inhibition of glomus cell acute responsiveness to hypoxia. Our observations indicate that Hif2α expression is required for the characteristic metabolic profile of glomus cells and provide a mechanistic explanation for the acute O2 regulation of breathing.

Release of CGRP in vivo from rat dura mater: Influence of capsaicin and topiramate

Introduction Migraine is a disease that stands out for its high prevalence with changes in the nervous system, abnormal levels of neurotransmitters, neuromodulators, and neuropeptides. The main mechanisms of action of capsaicin are chemical induction through the activation of TRPV1 channels, allowing calcium influx into neurons in the trigeminal ganglion of the dura mater, activating mast cell degranulation, releasing pro-inflammatory (e.g., histamine, oxide nitric) and vasoactive (e.g., CGRP and substance P) substances. For treatment, classes of drugs are used to act on blood vessels and to prevent vasodilation, as well as depolarization of sensory fibers of the dura mater. Objectives To better understand sterile inflammation after exposing the dura mater bilaterally, we created an experimental model to study mechanisms of action of topiramate and capsaicin in mast cell degranulation and release of CGRP in a rat skull preparation in vivo using anesthetized animals. Methods Thirty-five Wistar rats were used, divided into two groups of chronic topiramate (GTC) treated with 20mg/kg/day, gavage/10 days, and acute topiramate (GTA) in situ in the dura mater (10-3M). The animals were anesthetized and cranial windows between the coronal and lambda sutures in the hemicraniums were performed with a drill to expose the dura mater bilaterally. 10-3M capsaicin was placed on the right side and synthetic interstitial fluid on the left side and exposed to contact for 10 minutes to a small cotton ball soaked with the respective solutions so that there is no leakage of the treatment, and posteriorly kept in the freezer (-20°C) for later quantification of CGRP. The percentage of degranulated mast cells was quantified after removal of the dura mater by staining it with toluidine blue. A commercial enzyme immunoassay quantified the release of CGRP from the cranial dura mater... (Too see the complet abstract, please, check out the PDF.)

A case of ischemic-hypoxic encephalopathy due to oral succinylcholine ingestion.

A case of ischemic-hypoxic encephalopathy due to oral succinylcholine ingestion.

On the molecular mechanism of excitation–transcription coupling in skeletal muscle

An important question in neuromuscular biology is how skeletal muscle cells decipher the stimulation pattern coming from motoneurons to define their phenotype-activating transcriptional changes in a process named excitation-transcription coupling. We have shown in adult muscle fibers that 20 Hz electrical stimulation (ES) activates a signaling cascade that starts with Cav1.1 activation, ATP release trough pannexin-1 channel, activation of purinergic receptors, and IP3-dependent Ca2+ signals inducing transcriptional changes related to muscle plasticity from fast to slow phenotype. Extracellular addition of 30 µM ATP mimics transcriptional changes induced by ES at 20 Hz. ATP release occurs in two peaks, the first around 15 s after ES and a second around 300 s after ES. In the present work, we used apyrase to hydrolyze ATP 60 s after ES, maintaining the first peak and eliminating the second peak. In this condition, transcriptional changes were abolished, indicating that the second peak is the one crucial to activate transcription. Additionally, we observed a small depolarization of fibers after ES. The addition of 30 to 100 µM external ATP also induced depolarization of muscle fibers. This depolarization was unable to activate contraction but was able to induce transcriptional changes induced by 20 Hz ES. These changes were completely inhibited by the IP3R blocker xestospongin B, suggesting that IP3-dependent events are triggered at these membrane depolarization values. Moreover, transcriptional changes induced by addition of 30 µM extracellular ATP was blocked by incubation of fibers with 25 µM Nifedipine. These results suggest that the second ATP peak observed after 20 Hz ES is responsible for transcriptional activation by inducing small depolarizations of fiber membranes that are also sensed by Cav1.1. Finally, we show evidence that downstream of purinergic receptors, PKC is activated, likely causing phosphorylation of ClC-1 chloride channels, possibly responsible for depolarization after 20 Hz.

Pannexin-1 and CaV1.1 show reciprocal interaction during excitation-contraction and excitation-transcription coupling in skeletal muscle.

One of the most important functions of skeletal muscle is to respond to nerve stimuli by contracting. This function ensures body movement but also participates in other important physiological roles, like regulation of glucose homeostasis. Muscle activity is closely regulated to adapt to different demands and shows a plasticity that relies on both transcriptional activity and nerve stimuli. These two processes, both dependent on depolarization of the plasma membrane, have so far been regarded as separated and independent processes due to a lack of evidence of common protein partners or molecular mechanisms. In this study, we reveal intimate functional interactions between the process of excitation-induced contraction and the process of excitation-induced transcriptional activity in skeletal muscle. We show that the plasma membrane voltage-sensing protein CaV1.1 and the ATP-releasing channel Pannexin-1 (Panx1) regulate each other in a reciprocal manner, playing roles in both processes. Specifically, knockdown of CaV1.1 produces chronically elevated extracellular ATP concentrations at rest, consistent with disruption of the normal control of Panx1 activity. Conversely, knockdown of Panx1 affects not only activation of transcription but also CaV1.1 function on the control of muscle fiber contraction. Altogether, our results establish the presence of bidirectional functional regulations between the molecular machineries involved in the control of contraction and transcription induced by membrane depolarization of adult muscle fibers. Our results are important for an integrative understanding of skeletal muscle function and may impact our understanding of several neuromuscular diseases.

Finite element analysis predicts Ca2+ microdomains within tubular-sarcoplasmic reticular junctions of amphibian skeletal muscle

A finite element analysis modelled diffusional generation of steady-state Ca2+ microdomains within skeletal muscle transverse (T)-tubular-sarcoplasmic reticular (SR) junctions, sites of ryanodine receptor (RyR)-mediated SR Ca2+ release. It used established quantifications of sarcomere and T-SR anatomy (radial diameter d=220 , mathrm{n}mathrm{m}; axial distance w=12 , mathrm{n}mathrm{m}). Its boundary SR Ca2+ influx densities,{J}_{mathrm{influx}}, reflected step impositions of influxes, it {Phi }_{mathrm{influx}}={J}_{mathrm{influx}}left(frac{pi {d}^{2}}{4}right), deduced from previously measured Ca2+ signals following muscle fibre depolarization. Predicted steady-state T-SR junctional edge [Ca2+], [Ca2+]edge, matched reported corresponding experimental cytosolic [Ca2+] elevations given diffusional boundary effluxit it {Phi }_{mathrm{efflux}}=frac{D [ {{{mathrm{Ca}}^{2+}}}]_{mathrm{edge}}}{lambda } (pi dw), established cytosolic Ca2+ diffusion coefficients (D = 4 times {10}^{7} mathrm{nm}^{2}/mathrm{s}) and exit length lambda = 9.2 , mathrm{n}mathrm{m}. Dependences of predicted [Ca2+]edge upon {J}_{mathrm{influx}} then matched those of experimental [Ca2+] upon Ca2+ release through their entire test voltage range. The resulting model consistently predicted elevated steady-state T-SR junctional ~ µM-[Ca2+] elevations radially declining from maxima at the T-SR junction centre along the entire axial T-SR distance. These [Ca2+] heterogeneities persisted through 104- and fivefold, variations in D and w around, and fivefold reductions in d below, control values, and through reported resting muscle cytosolic [Ca2+] values, whilst preserving the flux conservation (it it {Phi }_{mathrm{influx}}={Phi }_{mathrm{efflux}}) condition, {left[mathrm{C}{mathrm{a}}^{2+}right]}_{mathrm{edge}}=frac{lambda {dJ}_{mathrm{influx}}}{4Dw}. Skeletal muscle thus potentially forms physiologically significant ~ µM-[Ca2+] T-SR microdomains that could regulate cytosolic and membrane signalling molecules including calmodulin and RyR, These findings directly fulfil recent experimental predictions invoking such Ca2+ microdomains in observed regulatory effects upon Na+ channel function, in a mechanism potentially occurring in similar restricted intracellular spaces in other cell types.

Light depolarization based on dispersion degree of polarization.

The dispersion degree of polarization, a new definition of the depolarization degree of partially polarized beams, is first proposed, to the best of our knowledge, to measure the performance of fiber depolarizers. First, the description of the polarization based on the Poincaré sphere is introduced. Then, the modified Delaunay triangulation algorithm is introduced, and the calculation formula of the dispersion degree of polarization is given based on this algorithm. The experimental device was set up, and the dispersion degree of polarization of the depolarized light after the fiber depolarizer was measured to be 47.3%. The components and proportions of polarization in the depolarized light were also obtained. Compared with the degree of polarization, the dispersion degree of polarization can quantitatively analyze the light polarization evaluation in the time dimension and provide a numerical reference for improving the depolarizer, thus increasing the fiber sensor's accuracy.

MO009NEUTRALIZATION OF UPAR WITH AN ANTI-UPAR ANTIBODY AMELIORATES RECURRENT FSGS SERA INDUCED PODOCYTE INJURY

Abstract Background and Aims The role of suPAR as a biomarker and/or causative factor in the pathogenesis of recurrent FSGS remains unclear (Harel E., et al. Transplantation 2020; 104:54-60). While anti-suPAR antibodies have been shown to block suPAR induced podocyte injury in mouse models of FSGS, this beneficial effect has not yet been demonstrated in FSGS patients. We report here the inhibitor effects of 2G10, a fully human anti-suPAR antibody that blocks the interaction of suPAR with the B3 integrin on podocytes. Method The immortalized podocyte cell line was developed by transfection with the temperature sensitive SV40 T gene. These cells proliferate at the “permissive” temperature (33°C) and are considered undifferentiated. After transferring to the “nonpermissive” temperature (37°C), they enter growth arrest and by day 10-14 express markers of differentiated podocytes in vivo, such as nephrin, podocin, CD2 associated protein (CD2AP), synaptopodin, and known molecules of the slit diaphragm ZO-1, α, β, and γ-catenin, and P-cadherin. The podocytes were cultured in RPMI medium supplemented with insulin, transferrin, selenium, sodium pyruvate (ITS-A, Gibco #513000), 10% FBS and penicillin/streptomycin. After differentiation for 14 days, cells were serum starved for 1h. Serum from rFSGS patients or from a control patient was added (4% final) and cells were cultured for an additional 24h. After fixation in PFA/sucrose. actin cytoskeleton was visualized by labeling with rhodamine-conjugated phalloidin. DAPI was used for nuclei staining. Cells were imaged by confocal microscopy at 40X magnification and the number of cells with intact stress fibers were counted. For rescue of stress fibers, podocytes were cultured in the presence of a fully humanized anti uPAR antibody (2G10, 1 ug/ml; Duriseti S, J Biol Chem, 2010, 285:26878-88) or an isotype IgG control antibody (1 ug/ml). Results Sera from three patients with recurrence of FSGS after transplant were used in the study. Podocyte culture in the presence of sera from all three patients caused significant depolarization of stress fibers as determined by number of stress fiber positive cells (30%, 59% and 49% reduction with respect to untreated podocytes respectively). Treatment of podocytes with control sera did not cause any significant changes (data not shown). Culture of podocytes with patient sera in the presence of 2G10 antibody against uPAR rescued stress fibers (Fig 1A and 1B). On the other hand, a control human IgG was unable to rescue the loss of stress fibers induced by sera from recurrent FSGS patients. Conclusion The therapeutic potential of a human anti-suPAR antibody in samples from patients with recurrent FSGS has not been previously demonstrated. The in vitro findings of 2G10 antibody on preserving the stress fibers in human podocytes from the disrupting effect of the sera of patients with recurrent FSGS suggest that antibodies that block suPAR could be effective in preventing recurrence of FSGS.

Muscle Velocity Recovery Cycles to Examine Muscle Membrane Properties.

Although conventional nerve conduction studies (NCS) and electromyography (EMG) are suitable for the diagnosis of neuromuscular disorders, they provide limited information about muscle fiber membrane properties and underlying disease mechanisms. Muscle velocity recovery cycles (MVRCs) illustrate how the velocity of a muscle action potential depends on the time after a preceding action potential. MVRCs are closely related to changes in membrane potential that follow an action potential, thereby providing information about muscle fiber membrane properties. MVRCs may be recorded quickly and easily by direct stimulation and recording from multi-fiber bundles in vivo. MVRCs have been helpful in understanding disease mechanisms in several neuromuscular disorders. Studies in patients with channelopathies have demonstrated the different effects of specific ion channel mutations on muscle excitability. MVRCs have been previously tested in patients with neurogenic muscles. In this prior study, muscle relative refraction period (MRRP) was prolonged, and early supernormality (ESN) and late supernormality (LSN) were reduced in patients compared to healthy controls. Thereby, MVRCs can provide in vivo evidence of membrane depolarization in intact human muscle fibers that underlie their reduced excitability. The protocol presented here describes how to record MVRCs and analyze the recordings. MVRCs can serve as a fast, simple, and useful method for revealing disease mechanisms across a broad range of neuromuscular disorders.

The pro-algesic effect of γ-aminobutyric acid (GABA) injection into the masseter muscle of healthy men and women.

Background and aims Preclinical studies have reported that activation of peripheral γ-aminobutyric acid A (GABAA) receptors may result in analgesia. The current study was conducted in young healthy men (n = 30) and women (n = 28) to determine whether injections of GABA into the masseter muscle reduce pain in a sex-related manner. Methods The effect of injection of GABA alone, or in combination with the non-inflammatory algogen glutamate, was assessed in two separate studies. Lorazepam, a positive allosteric modulator of the GABAA-receptor, was co-injected with GABA in both studies to explore the role of this receptor in muscle pain responses of healthy human volunteers. Masticatory muscle mechanical pain intensity was recorded on an electronic visual analogue scale (VAS) while muscle pain sensitivity was assessed by determining the pressure pain threshold (PPT), tolerance and maximal jaw opening (MJO) of the subjects prior to, and again after the various intramuscular injections. Results Intramuscular injection of GABA alone was reported to be significantly more painful, in a concentration related manner, than saline control injections, and this pain was further increased by co-injection of lorazepam with GABA. Co-injection of GABA with glutamate was found to significantly increase glutamate-evoked masseter muscle pain in men, but not in women. There was no effect of injections of either GABA alone, or GABA with glutamate, on PPT, tolerance or maximum jaw opening. Conclusions Injection of GABA into the human masseter muscle appears to excite nociceptors to produce muscle pain without a longer term effect on mechanical pain sensitivity in the muscle. The findings suggest that GABA-mediated pain in humans is produced through peripheral GABAA receptor activation. The mechanism underlying the sex-related difference in the effect of GABA on glutamate-evoked muscle pain was speculated to be due to a methodological artifact. Implications This study was designed to detect analgesic rather than algesic effects of peripherally administered GABA, and as a result, the concentration of glutamate chosen for injection was close to the maximal pain response for healthy women, based on previously determined pain-concentration response relationships for glutamate. This may explain the finding of greater pain in men than women, when GABA and glutamate were co-injected. Overall, the findings suggest that activation of peripheral GABAA receptors in human masticatory muscle produces pain, possibly due to depolarization of the masticatory muscle afferent fibers.

1947-P: Comparative Effects of PCSK9 Inhibitor and High-Dose Atorvastatin on Mitochondria of Red Muscle Fibers in Obese Female Rats

Obesity and dyslipidemia cause mitochondrial dysfunction of skeletal muscle. Low dose atorvastatin impairs mitochondrial function of white muscle fibers but does not damage that of red muscle fibers. However, the effects of PCSK9 inhibitors and high dose atorvastatin on mitochondrial function of red muscle fibers have not been identified. Twenty-four female rats (180-200 g) were divided into 2 groups. Six rats were fed with normal diet (ND) and 18 rats were fed with high-fat diet (HFD) for 15 weeks. At week 12, ND-fed rats were treated with vehicle (NDV), while HFD-fed rats were equally subdivided and treated with either vehicle (HFV), 4 mg/kg/day of PCSK9 inhibitor (HFP), or 40 mg/kg/day of atorvastatin (HFA) for another 3 weeks. HFV rats developed obesity and dyslipidemia, as indicated by increased weight, visceral fat, and total cholesterol. Treatment with atorvastatin and PCSK9 inhibitor improved obesity and dyslipidemia. Increased lipid peroxidation (MDA), mitochondrial fission (pDrp1/Drp1), mitochondrial ROS production, and mitochondrial membrane depolarization were found in soleus muscle of HFV rats. Treatment with atorvastatin and PCSK9 inhibitor similarly improved lipid peroxidation and mitochondrial fission. However, only PCSK9 inhibitor improved mitochondrial ROS production and mitochondrial membrane depolarization. Our findings suggest that obesity increases lipid peroxidation, mitochondrial fission, mitochondrial ROS production, and mitochondrial membrane depolarization in red muscle fibers. PCSK9 inhibitor attenuates those deleterious effects of obesity. High dose atorvastatin improves lipid peroxidation and mitochondrial fission, but does not attenuate obesity-induced mitochondrial ROS production and mitochondrial membrane depolarization in red muscle fibers. The results imply that high dose atorvastatin causes adverse effects on red muscle fibers despite its benefit on the improvement of obesity and dyslipidemia. Disclosure C. Thonusin: None. S. Palee: None. B. Arunsak: None. P. Amput: None. W. Pratchayasakul: None. N. Chattipakorn: None. S.C. Chattipakorn: None. Funding Thailand Research Fund

Diseño de un Prototipo de Electroestimulación Neuromuscular de Baja Frecuencia

Objective. Design a low frequency Neuromuscular Electrostimulation prototype with modifiable digital parameters through the Arduino platform. Methodology: The following work shows the design of a low-frequency neuromuscular electrostimulation equipment prototype with similar characteristics to conventional devices but with a unique design in its programming, this prototype allows modifying the parameters of intensity, time, pulse duration and Frequency through the Arduino platform, this HARDWARE is based on simple analog and digital boards that allow reading input and output data on the device. This prototype emits a symmetrical biphasic current of rectangular pulses and although there is a great variety of currents within the Neuromuscular Electrostimulation (EENM) focused on improving and maximizing the activation of a muscle, generally the symmetric biphasic pulses are better tolerated to the passage of a current through subcutaneous tissue, with greater effectiveness in depolarization of thick fibers of intact nerves. Contribution: To offer alternatives for the management of digital devices in electrotherapy.

To flourish or perish: evolutionary TRiPs into the sensory biology of plant-herbivore interactions.

The interactions between plants and their herbivores are highly complex systems generating on one side an extraordinary diversity of plant protection mechanisms and on the other side sophisticated consumer feeding strategies. Herbivores have evolved complex, integrative sensory systems that allow them to distinguish between food sources having mere bad flavors from the actually toxic ones. These systems are based on the senses of taste, olfaction and somatosensation in the oral and nasal cavities, and on post-ingestive chemosensory mechanisms. The potential ability of plant defensive chemical traits to induce tissue damage in foragers is mainly encoded in the latter through chemesthetic sensations such as burning, pain, itch, irritation, tingling, and numbness, all of which induce innate aversive behavioral responses. Here, we discuss the involvement of transient receptor potential (TRP) channels in the chemosensory mechanisms that are at the core of complex and fascinating plant-herbivore ecological networks. We review how "sensory" TRPs are activated by a myriad of plant-derived compounds, leading to cation influx, membrane depolarization, and excitation of sensory nerve fibers of the oronasal cavities in mammals and bitter-sensing cells in insects. We also illustrate how TRP channel expression patterns and functionalities vary between species, leading to intriguing evolutionary adaptations to the specific habitats and life cycles of individual organisms.

NaV1.4 DI-S4 periodic paralysis mutation R222W enhances inactivation and promotes leak current to attenuate action potentials and depolarize muscle fibers

Hypokalemic periodic paralysis is a skeletal muscle disease characterized by episodic weakness associated with low serum potassium. We compared clinical and biophysical effects of R222W, the first hNaV1.4 domain I mutation linked to this disease. R222W patients exhibited a higher density of fibers with depolarized resting membrane potentials and produced action potentials that were attenuated compared to controls. Functional characterization of the R222W mutation in heterologous expression included the inactivation deficient IFM/QQQ background to isolate activation. R222W decreased sodium current and slowed activation without affecting probability. Consistent with the phenotype of muscle weakness, R222W shifted fast inactivation to hyperpolarized potentials, promoted more rapid entry, and slowed recovery. R222W increased the extent of slow inactivation and slowed its recovery. A two-compartment skeletal muscle fiber model revealed that defects in fast inactivation sufficiently explain action potential attenuation in patients. Molecular dynamics simulations showed that R222W disrupted electrostatic interactions within the gating pore, supporting the observation that R222W promotes omega current at hyperpolarized potentials. Sodium channel inactivation defects produced by R222W are the primary driver of skeletal muscle fiber action potential attenuation, while hyperpolarization-induced omega current produced by that mutation promotes muscle fiber depolarization.

Long-term effects of direct current are reproduced by intermittent depolarization of myelinated nerve fibers.

Direct current (DC) potently increases the excitability of myelinated afferent fibers in the dorsal columns, both during DC polarization of these fibers and during a considerable (>1 h) postpolarization period. The aim of the present study was to investigate whether similarly long-lasting changes in the excitability of myelinated nerve fibers in the dorsal columns may be evoked by field potentials following stimulation of peripheral afferents and by subthreshold epidurally applied current pulses. The experiments were performed in deeply anesthetized rats. The effects were monitored by changes in nerve volleys evoked in epidurally stimulated hindlimb afferents and in the synaptic actions of these afferents. Both were found to be facilitated during as well as following stimulation of a skin nerve and during as well as following epidurally applied current pulses of 5- to 10-ms duration. The facilitation occurring ≤2 min after skin nerve stimulation could be linked to both primary afferent depolarization and large dorsal horn field potentials, whereas the subsequent changes (up to 1 h) were attributable to effects of the field potentials. The findings lead to the conclusion that the modulation of spinal activity evoked by DC does not require long-lasting polarization and that relatively short current pulses and intrinsic field potentials may contribute to plasticity in spinal activity. These results suggest the possibility of enhancing the effects of epidural stimulation in human subjects by combining it with polarizing current pulses and peripheral afferent stimulation and not only with continuous DC. NEW & NOTEWORTHY The aim of this study was to define conditions under which a long-term increase is evoked in the excitability of myelinated nerve fibers. The results demonstrate that a potent and long-lasting increase in the excitability of afferent fibers traversing the dorsal columns may be induced by synaptically evoked intrinsic field as well as by epidurally applied intermittent current pulses. They thus provide a new means for the facilitation of the effects of epidural stimulation.

A Type of Lyot Fiber Depolarizer Based on Photonic Crystal Fiber

In this letter, we utilize the beam-propagation method to design and simulate a high-birefringence square-lattice polarization microstructure to realize 45-degree rotation when light passes through, and confirm its arrangement and parameters. Optical parameters in allusion to polarization controller of photonic crystal fiber such as birefringence characteristics have been studied, and optical simulation of the polarization microstructure of the depolarized Lyot photonic crystal has been performed.

Characterization of a NaV1.4 Hypokalemic Periodic Paralysis Mutation in Domain I

We characterized the clinical effects and biophysical properties of hypokalemic periodic paralysis mutation, R222W, initially identified in Korean patients. The heterozygous mutation was also found in a 52 year-old patient with weakness beginning at age 18 and associated with mild hypokalemia, and associated with myalgia. R222W muscle fibers exhibited action potentials with attenuated height, and slowed rate of rise compared to those from a control patient. Membrane potential recordings in normal potassium showed that R222W fibers exhibited a greater density of depolarized potentials (P2) compared to controls. R222W was functionally characterized with cut-open oocyte voltage clamp recordings at 20 °C. The mutation produced a depolarizing shift of the activation midpoint; this effect was shown to be indirect by comparing wild type and R222W channels in the IFM/QQQ inactivation deficient background. R222W produced several effects on inactivation consistent with hypoexcitability. Compared to wild type hNaV1.4, R222W produced a left-shift of the steady-state fast inactivation curve, accelerated entry, and slowed recovery. R222W also produced more complete slow inactivation and slowed its recovery. At hyperpolarized voltages, R222W promoted a cationic omega current, which may explain the paradoxical depolarization of muscle fibers. This work was supported by NIH 1R15NS093579-01A1 to JRG, NIH NIGMS P20GM103498 to ISU, the non-profit Else-Kroner-Fresenius Foundation, German DGM Muscle Disease Society, Taro Pharmaceuticals, and the German BMBF Ministry for IonNeurOnet project jointly to KJR and FLH.