Electrophysiological Properties Research Articles

Unlocking the therapeutic potential of TRPV3: Insights into thermosensation, channel modulation, and skin homeostasis involving TRPV3.

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

Hypothalamic vasopressin sex differentiation is observed by embryonic day 15 in mice and is disrupted by the xenoestrogen bisphenol A

Arginine vasopressin (AVP) neurons of the hypothalamic paraventricular region (AVPPVN) mediate sex-biased social behaviors across most species, including mammals. In mice, neural sex differences are thought to be established during a critical window around birth ( embryonic (E) day 18 to postnatal (P) day 2) whereby circulating testosterone from the fetal testis is converted to estrogen in sex-dimorphic brain regions. Here, we found that AVPPVN neurons are sexually dimorphic by E15.5, prior to this critical window, and that gestational bisphenol A (BPA) exposure permanently masculinized female AVPPVN neuronal numbers, projections, and electrophysiological properties, causing them to display male-like phenotypes into adulthood. Moreover, we showed that nearly twice as many neurons that became AVP+ by P0 were born at E11 in males and BPA-exposed females compared to control females, suggesting that AVPPVN neuronal masculinization occurs between E11 and P0. We further narrowed this sensitive period to around the timing of neurogenesis by demonstrating that exogenous estrogen exposure from E14.5 to E15.5 masculinized female AVPPVN neuronal numbers, whereas a pan-estrogen receptor antagonist exposed from E13.5 to E15.5 blocked masculinization of males. Finally, we showed that restricting BPA exposure to E7.5-E15.5 caused adult females to display increased social dominance over control females, consistent with an acquisition of male-like behaviors. Our study reveals an E11.5 to E15.5 window of estrogen sensitivity impacting AVPPVN sex differentiation, which is impacted by prenatal BPA exposure.

The Concise Language Paradigm (CLaP), a framework for studying the intersection of comprehension and production: electrophysiological properties.

Studies investigating language commonly isolate one modality or process, focusing on comprehension or production. Here, we present a framework for a paradigm that combines both: the Concise Language Paradigm (CLaP), tapping into comprehension and production within one trial. The trial structure is identical across conditions, presenting a sentence followed by a picture to be named. We tested 21 healthy speakers with EEG to examine three time periods during a trial (sentence, pre-picture interval, picture onset), yielding contrasts of sentence comprehension, contextually and visually guided word retrieval, object recognition, and naming. In the CLaP, sentences are presented auditorily (constrained, unconstrained, reversed), and pictures appear as normal (constrained, unconstrained, bare) or scrambled objects. Imaging results revealed different evoked responses after sentence onset for normal and time-reversed speech. Further, we replicated the context effect of alpha-beta power decreases before picture onset for constrained relative to unconstrained sentences, and could clarify that this effect arises from power decreases following constrained sentences. Brain responses locked to picture-onset differed as a function of sentence context and picture type (normal vs. scrambled), and naming times were fastest for pictures in constrained sentences, followed by scrambled picture naming, and equally fast for bare and unconstrained picture naming. Finally, we also discuss the potential of the CLaP to be adapted to different focuses, using different versions of the linguistic content and tasks, in combination with electrophysiology or other imaging methods. These first results of the CLaP indicate that this paradigm offers a promising framework to investigate the language system.

Left Atrial Electrophysiological Properties after Pulmonary Vein Isolation Predict the Recurrence of Atrial Fibrillation: A Cohort Study

Left Atrial Electrophysiological Properties after Pulmonary Vein Isolation Predict the Recurrence of Atrial Fibrillation: A Cohort Study

Reduction of APOE accounts for neurobehavioral deficits in fetal alcohol spectrum disorders.

A hallmark of fetal alcohol spectrum disorders (FASD) is neurobehavioral deficits that still do not have effective treatment. Here, we present that reduction of Apolipoprotein E (APOE) is critically involved in neurobehavioral deficits in FASD. We show that prenatal alcohol exposure (PAE) changes chromatin accessibility of Apoe locus, and causes reduction of APOE levels in both the brain and peripheral blood in postnatal mice. Of note, postnatal administration of an APOE receptor agonist (APOE-RA) mitigates motor learning deficits and anxiety in those mice. Several molecular and electrophysiological properties essential for learning, which are altered by PAE, are restored by APOE-RA. Our human genome-wide association study further reveals that the interaction of PAE and a single nucleotide polymorphism in the APOE enhancer which chromatin is closed by PAE in mice is associated with lower scores in the delayed matching-to-sample task in children. APOE in the plasma is also reduced in PAE children, and the reduced level is associated with their lower cognitive performance. These findings suggest that controlling the APOE level can serve as an effective treatment for neurobehavioral deficits in FASD.

The Effect of Calcium Ions on the Electrophysiological Properties of Single ANO6 Channels.

Proteins belonging to the anoctamin (ANO) family form calcium-activated chloride channels (CaCCs). The most unusual member of this family, ANO6 (TMEM16F), simultaneously exhibits the functions of calcium-dependent scramblase and the ion channel. ANO6 affects the plasma membrane dynamics and phosphatidylserine transport; it is also involved in programmed cell death. The properties of ANO6 channels remain the subject of debate. In this study, we investigated the effect of variations in the intracellular and extracellular concentrations of calcium ions on the electrophysiological properties of endogenous ANO6 channels by recording single ANO6 channels. It has been demonstrated that (1) a high calcium concentration in an extracellular solution increases the activity of endogenous ANO6 channels, (2) the permeability of endogenous ANO6 channels for chloride ions is independent of the extracellular concentration of calcium ions, (3) that an increase in the intracellular calcium concentration leads to the activation of endogenous ANO6 channels with double amplitude, and (4) that the kinetics of the channel depend on the plasma membrane potential rather than the intracellular concentration of calcium ions. Our findings give grounds for proposing new mechanisms for the regulation of the ANO6 channel activity by calcium ions both at the inner and outer sides of the membrane.

Pulsed electromagnetic field-assisted reduced graphene oxide composite 3D printed nerve scaffold promotes sciatic nerve regeneration in rats

Peripheral nerve injuries can lead to sensory or motor deficits that have a serious impact on a patient’s mental health and quality of life. Nevertheless, it remains a major clinical challenge to develop functional nerve conduits as an alternative to autologous grafts. We applied reduced graphene oxide (rGO) as a bioactive conductive material to impart electrophysiological properties to a 3D printed scaffold and the application of a pulsed magnetic field to excite the formation of microcurrents and induce nerve regeneration. In vitro studies showed that the nerve scaffold and the pulsed magnetic field made no effect on cell survival, increased S-100β protein expression, enhanced cell adhesion, and increased the expression level of nerve regeneration-related mRNAs. In vivo experiments suggested that the protocol was effective in promoting nerve regeneration, resulting in functional recovery of sciatic nerves in rats, when they were damaged close to that of the autologous nerve graft, and increased expression of S-100β, NF200, and GAP43. These results indicate that rGO composite nerve scaffolds combined with pulsed magnetic field stimulation have great potential for peripheral nerve rehabilitation.

Generation of a Human Induced Pluripotent Stem Cell Line Expressing a Magnetic Resonance Imaging Reporter Gene.

The objective of the current study is to develop a new method for tracking transplanted human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) using magnetic resonance imaging (MRI). The CRISPR/dCas9 activation system is employed to overexpress ferritin heavy chain (FHC) in hiPSC-CMs. The mRNA and protein expression of FHC in hiPSC and hiPSC-CMs significantly increased after transfection. Iron chloride does not affect the cell viability in a concentration range from 0 to 2000 µm. hiPSCs overexpressing FHC (hiPSC- FHCOE) and hiPSC-CMs overexpressing FHC (hiPSC-CM-FHCOE) significantly enhanced cellular uptake of iron chloride but with no changes in electrophysiological properties compared to hiPSC-CM-Control. Furthermore, hiPSC-CM-FHCOE presented robust contrast and lower T2* values, signifying their potential as highly effective candidates for cardiac MRI. Next, hiPSC-CM-FHCOE is injected into mouse hearts and after 3 days of transplantation, MR images are obtained. hiPSC-CM-FHCOE cells exhibited clear signals in the hearts with lower T2* and rapid signal decay. Collectively, data from this proof-of-concept study demonstrated that endogenous labeling with FHC in hiPSC-CMs can be a potent strategy for enhancing the accuracy of cardiac MRI. This technology represents a significant step forward in tracking the transplanted hiPSC-CMs in the hearts of live animals.

Unique electrophysiological property of a novel Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker, ANP-230

Voltage-gated sodium channel subtypes, Nav1.7, Nav1.8, and Nav1.9 are predominantly expressed in peripheral sensory neurons. Recent genetic studies have revealed that they are involved in pathological pain processing and that the blockade of Nav1.7, Nav1.8, or Nav1.9 will become a promising pharmacotherapy especially for neuropathic pain. A growing number of drug discovery programs have targeted either of the subtypes to obtain a selective inhibitor which can provide pain relief without affecting the cardiovascular and central nervous systems, though none of them has been approved yet. Here we describe the in vitro characteristics of ANP-230, a novel sodium channel blocker under clinical development. Surprisingly, ANP-230 was shown to block three pain-related subtypes, human Nav1.7, Nav1.8, and Nav1.9 with similar potency, but had only low inhibitory activity to human cardiac Nav1.5 channel and rat central Nav channels. The voltage clamp experiments using different step pulse protocols revealed that ANP-230 had a “tonic block” mode of action without state- and use-dependency. In addition, ANP-230 caused a depolarizing shift of the activation curve and decelerated gating kinetics in human Nav1.7-stably expressing cells. The depolarizing shift of activation curve was commonly observed in human Nav1.8-stably expressing cells as well as rat dorsal root ganglion neurons. These data suggested a quite unique mechanism of Nav channel inhibition by ANP-230. Finally, ANP-230 reduced excitability of rat dorsal root ganglion neurons in a concentration dependent manner. Collectively, these promising results indicate that ANP-230 could be a potent drug for neuropathic pain.

ForCEPSS—A framework for cardiac electrophysiology simulations standardization

Background and Objective:Simulation of cardiac electrophysiology (CEP) is an important research tool that is increasingly being adopted in industrial and clinical applications. Typical workflows for CEP simulation consist of a sequence of processing stages starting with building an anatomical model and then calibrating its electrophysiological properties to match observable data. While the calibration stages are common and generalizable, most CEP studies re-implement these steps in complex and highly variable workflows. This lack of standardization renders the execution of computational CEP studies in an efficient, robust, and reproducible manner a significant challenge. Here, we propose ForCEPSS as an efficient and robust, yet flexible, software framework for standardizing CEP simulation studies. Methods and Results:Key processing stages of CEP simulation studies are identified and implemented in a standardized workflow that builds on openCARP11https://opencarp.org/. Plank et al. (2021) and the Python-based carputils22https://git.opencarp.org/openCARP/carputils. framework. Stages include (i) the definition and initialization of action potential phenotypes, (ii) the tissue scale calibration of conduction properties, (iii) the functional initialization to approximate a limit cycle corresponding to the dynamic reference state according to an experimental protocol, and, (iv) the execution of the CEP study where the electrophysiological response to a perturbation of the limit cycle is probed. As an exemplar application, we employ ForCEPSS to prepare a CEP study according to the Virtual Arrhythmia Risk Prediction protocol used for investigating the arrhythmogenic risk of developing infarct-related ventricular tachycardia (VT) in ischemic cardiomyopathy patients. We demonstrate that ForCEPSS enables a fully automated execution of all stages of this complex protocol. Conclusion:ForCEPSS offers a novel comprehensive, standardized, and automated CEP simulation workflow. The high degree of automation accelerates the execution of CEP simulation studies, reduces errors, improves robustness, and makes CEP studies reproducible. Verification of simulation studies within the CEP modeling community is thus possible. As such, ForCEPSS makes an important contribution towards increasing transparency, standardization, and reproducibility of in silico CEP experiments.

Antiarrhythmic and Anti-Inflammatory Effects of Sacubitril/Valsartan on Post-Myocardial Infarction Scar.

Sacubitril/valsartan (Sac/Val) is superior to angiotensin-converting enzyme inhibitors in reducing the risk of heart failure hospitalization and cardiovascular death, but its mechanistic data on myocardial scar after myocardial infarction (MI) are lacking. The objective of this work was to assess the effects of Sac/Val on inflammation, fibrosis, electrophysiological properties, and ventricular tachycardia inducibility in post-MI scar remodeling in swine. After MI, 22 pigs were randomized to receive β-blocker (BB; control, n=8) or BB+Sac/Val (Sac/Val, n=9). The systemic immune response was monitored. Cardiac magnetic resonance data were acquired at 2-day and 29-day post MI to assess ventricular remodeling. Programmed electrical stimulation and high-density mapping were performed at 30-day post MI to assess ventricular tachycardia inducibility. Myocardial samples were collected for histological analysis. Compared with BB, BB+Sac/Val reduced acute circulating leukocytes (P=0.009) and interleukin-12 levels (P=0.024) at 2-day post MI, decreased C-C chemokine receptor type 2 expression in monocytes (P=0.047) at 15-day post MI, and reduced scar mass (P=0.046) and border zone mass (P=0.043). It also lowered the number and mass of border zone corridors (P=0.020 and P=0.05, respectively), scar collagen I content (P=0.049), and collagen I/III ratio (P=0.040). Sac/Val reduced ventricular tachycardia inducibility (P=0.026) and the number of deceleration zones (P=0.016). After MI, compared with BB, BB+Sac/Val was associated with reduced acute systemic inflammatory markers, reduced total scar and border zone mass on late gadolinium-enhanced magnetic resonance imaging, and lower ventricular tachycardia inducibility.

Novel Electrophysiological Signatures of Learning and Forgetting in Human REM Sleep.

Despite the known behavioral benefits of rapid eye movement (REM) sleep, discrete neural oscillatory events in human scalp electroencephalography (EEG) linked with behavior have not been discovered. This knowledge gap hinders mechanistic understanding of the function of sleep, as well as the development of biophysical models and REM-based causal interventions. We designed a detection algorithm to identify bursts of activity in high-density, scalp EEG within theta (4-8 Hz) and alpha (8-13 Hz) bands during REM sleep. Across 38 nights of sleep, we characterized the burst events (i.e., count, duration, density, peak frequency, amplitude) in healthy, young male and female human participants (38; 21F) and investigated burst activity in relation to sleep-dependent memory tasks: hippocampal-dependent episodic verbal memory and non-hippocampal visual perceptual learning. We found greater burst count during the more REM-intensive second half of the night (p < .05), longer burst duration during the first half of the night (p < .05), but no differences across the night in density or power (p > .05). Moreover, increased alpha burst power was associated with increased overnight forgetting for episodic memory (p < .05). Furthermore, we show that increased REM theta burst activity in retinotopically specific regions was associated with better visual perceptual performance. Our work provides a critical bridge between discrete REM sleep events in human scalp EEG that support cognitive processes, and the identification of similar activity patterns in animals models that allow for further mechanistic characterization.Significance Statement Current understanding of sleep and its role cognitive processes is incomplete due to a lack of discrete electrophysiological events in human rapid eye movement (REM) sleep detectable via scalp EEG. Our work remedies this gap in knowledge by designing an open-source, computational approach to identify electrophysiological alpha and theta burst events in REM sleep. Additionally, we provide evidence that these burst events are functionally important for learning and memory. Defining burst events in human REM will contribute to the development of a comprehensive mechanistic model of how sleep as a whole, and REM specifically, facilitate cognitive processes, and provide a deeper understanding of the fundamental electrophysiological properties of REM sleep that are distinct from non-REM sleep.

Electrophysiological properties of dorsal root ganglion neurons cultured on 3D silicon micro-pillar substrates

BackgroundSilicon-based micro-pillar substrates (MPS), as three-dimensional cell culture platforms with vertically aligned micro-patterned scaffolding structures, are known to facilitate high-quality growth and morphology of dorsal root ganglion (DRG) sensory neurons, promote neurite outgrowth and enhance neurite alignment. However, the electrophysiological aspects of DRG neurons cultured on silicon MPSs have not been thoroughly investigated, which is of greatest importance to ensure that such substrates do not disrupt neuronal homeostasis and function before their widespread adoption in diverse biomedical applications. New methodWe conducted whole-cell patch-clamp recordings to explore the electrophysiological properties of DRG neurons cultured on MPS arrays, utilizing a custom-made upright patch-clamp setup. ResultsOur findings revealed that DRG neurons exhibited similar electrophysiological responses on patterned MPS samples when compared to the control planar glass surfaces. Notably, there were no significant differences observed in the action potential parameters or firing patterns of action potentials between neurons grown on either substrate. Comparison with existing methodsIn the current study we for the first time confirmed that successful electrophysiological recordings can be obtained from the cells grown on MPS. ConclusionOur results imply that, despite the potential alterations caused by the cumulative trauma of tissue harvest and cell dissociation, essential functional cell properties of DRG neurons appear to be relatively maintained on MPS surfaces. Therefore, vertically aligned silicon MPSs could be considered as a potentially effective three-dimensional system for supporting a controlled cellular environment in culture.

Dielectrophoretic Characterization and Computational Analysis of Peripheral Blood Mononuclear Cells from MMTV-PyMT Mammary Carcinoma Models for Late Carcinoma Detection

Breast cancer is the leading cancer in women, with 284,200 new cases and an estimated 43,600 deaths in 2021. Early detection and proper treatment can enhance outcomes. This study probes the dielectric properties of peripheral blood mononuclear cells (PBMCs) from MMTV-PyMT mice at 14+ weeks (stage IV) using a microfluidic platform for early breast cancer detection. The central hypothesis is that changes in subcellular components like the cytoskeleton, membrane, cytoplasm, and extracellular matrix at carcinoma onset regulate dielectric properties (conductivity, permittivity), affecting bioelectric signals that aid cancer detection. This is based on preliminary data showing unique PBMC dielectric properties from WT and PyMT tumor-bearing mice, identifying bioelectric signals regulating human adenocarcinoma cells. We hypothesize isolated PBMCs are altered in cancer compared to healthy bodies, evident in the MMTV-PyMT mouse model for analyzing human breast cancer mechanisms. Although specific PBMC change mechanisms are not investigated, we hypothesize these alterations can be detected using dielectrophoresis, a dielectric characterization technique utilizing non-uniform electric fields to manipulate and separate normal and cancer cells based on differing electrophysiological plasma membrane properties. Our results present dielectric properties of murine PyMT and WT PBMCs exhibiting unique cellular behavior, with numerical simulations validating these results. These unique characteristics can discriminate between cancer and non-cancer cells. This novel, label-free, rapid (~2 min), low-cost cell sorting technology detects and separates early and late breast cancer stages, leading to preclinical development and future clinical trials. The long-term goal is a non-invasive tool to determine breast cancer at earliest stages without false positives/negatives of standard mammography screening

Reimagining Cortical Connectivity by Deconstructing Its Molecular Logic into Building Blocks.

Comprehensive maps of neuronal connectivity provide a foundation for understanding the structure of neural circuits. In a circuit, neurons are diverse in morphology, electrophysiology, gene expression, activity, and other neuronal properties. Thus, constructing a comprehensive connectivity map requires associating various properties of neurons, including their connectivity, at cellular resolution. A commonly used approach is to use the gene expression profiles as an anchor to which all other neuronal properties are associated. Recent advances in genomics and anatomical techniques dramatically improved the ability to determine and associate the long-range projections of neurons with their gene expression profiles. These studies revealed unprecedented details of the gene-projection relationship, but also highlighted conceptual challenges in understanding this relationship. In this article, I delve into the findings and the challenges revealed by recent studies using state-of-the-art neuroanatomical and transcriptomic techniques. Building upon these insights, I propose an approach that focuses on understanding the gene-projection relationship through basic features in gene expression profiles and projections, respectively, that associate with underlying cellular processes. I then discuss how the developmental trajectories of projections and gene expression profiles create additional challenges and necessitate interrogating the gene-projection relationship across time. Finally, I explore complementary strategies that, together, can provide a comprehensive view of the gene-projection relationship.

GADD45B in the ventral hippocampal CA1 modulates aversive memory acquisition and spatial cognition

AimsThis study was designed to investigate the role of growth arrest and DNA damage-inducible β (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. Main methodsAdeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. Key findingsKnockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. SignificanceThese results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition.

Elevated interleukin-8 expression by skin fibroblasts as a potential contributor to pain in women with Fabry disease.

Fabry disease (FD) is a lysosomal storage disorder of X-linked inheritance. Mutations in the α-galactosidase A gene lead to cellular globotriaosylceramide (Gb3) depositions and triggerable acral burning pain in both sexes as an early FD symptom of unknown pathophysiology. We aimed at elucidating the link between skin cells and nociceptor sensitization contributing to FD pain in a sex-associated manner. We used cultured keratinocytes and fibroblasts of 27 adult FD patients and 20 healthy controls. Epidermal keratinocytes and dermal fibroblasts were cultured and immunoreacted to evaluate Gb3 load. Gene expression analysis of pain-related ion channels and pro-inflammatory cytokines was performed in dermal fibroblasts. We further investigated electrophysiological properties of induced pluripotent stem cell (iPSC) derived sensory-like neurons of a man with FD and a healthy man and incubated the cells with interleukin 8 (IL-8) or fibroblast supernatant as an in vitro model system. Keratinocytes displayed no intracellular, but membrane-bound Gb3 deposits. In contrast, fibroblasts showed intracellular Gb3 and revealed higher gene expression of potassium intermediate/small conductance calcium-activated potassium channel 3.1 (KCa 3.1, KCNN4) in both, men and women with FD compared to controls. Additionally, cytokine expression analysis showed increased IL-8 RNA levels only in female FD fibroblasts. Patch-clamp studies revealed reduced rheobase currents for both iPSC neuron cell lines incubated with IL-8 or fibroblast supernatant of women with FD. We conclude that Gb3 deposition in female FD patient skin fibroblasts may lead to increased KCa3.1 activity and IL-8 secretion. This may result in cutaneous nociceptor sensitization as a potential mechanism contributing to a sex-associated FD pain phenotype.

Transmembrane proteins with unknown function (TMEMs) as ion channels: electrophysiological properties, structure, and pathophysiological roles.

A transmembrane (TMEM) protein with an unknown function is a type of membrane-spanning protein expressed in the plasma membrane or the membranes of intracellular organelles. Recently, several TMEM proteins have been identified as functional ion channels. The structures and functions of these proteins have been extensively studied over the last two decades, starting with TMEM16A (ANO1). In this review, we provide a summary of the electrophysiological properties of known TMEM proteins that function as ion channels, such as TMEM175 (KEL), TMEM206 (PAC), TMEM38 (TRIC), TMEM87A (GolpHCat), TMEM120A (TACAN), TMEM63 (OSCA), TMEM150C (Tentonin3), and TMEM43 (Gapjinc). Additionally, we examine the unique structural features of these channels compared to those of other well-known ion channels. Furthermore, we discuss the diverse physiological roles of these proteins in lysosomal/endosomal/Golgi pH regulation, intracellular Ca2+ regulation, spatial memory, cell migration, adipocyte differentiation, and mechanical pain, as well as their pathophysiological roles in Parkinson's disease, cancer, osteogenesis imperfecta, infantile hypomyelination, cardiomyopathy, and auditory neuropathy spectrum disorder. This review highlights the potential for the discovery of novel ion channels within the TMEM protein family and the development of new therapeutic targets for related channelopathies.

Electrophysiological Properties of Proprioception-Related Neurons in the Intermediate Thoracolumbar Spinal Cord.

Proprioception, the sense of limb and body position, is required to produce accurate and precise movements. Proprioceptive sensory neurons transmit muscle length and tension information to the spinal cord. The function of excitatory neurons in the intermediate spinal cord, which receive this proprioceptive information, remains poorly understood. Using genetic labeling strategies and patch-clamp techniques in acute spinal cord preparations in mice, we set out to uncover how two sets of spinal neurons, Clarke's column (CC) and Atoh1-lineage neurons, respond to electrical activity and how their inputs are organized. Both sets of neurons are located in close proximity in laminae V-VII of the thoracolumbar spinal cord and have been described to receive proprioceptive signals. We find that a majority of CC neurons have a tonic-firing type and express a distinctive hyperpolarization-activated current (Ih). Atoh1-lineage neurons, which cluster into two spatially distinct populations, are mostly a fading-firing type and display similar electrophysiological properties to each other, possibly due to their common developmental lineage. Finally, we find that CC neurons respond to stimulation of lumbar dorsal roots, consistent with prior knowledge that CC neurons receive hindlimb proprioceptive information. In contrast, using a combination of electrical stimulation, optogenetic stimulation, and transsynaptic rabies virus tracing, we find that Atoh1-lineage neurons receive heterogeneous, predominantly local thoracic inputs that include parvalbumin-lineage sensory afferents and local interneuron presynaptic inputs. Altogether, we find that CC and Atoh1-lineage neurons have distinct membrane properties and sensory input organization, representing different subcircuit modes of proprioceptive information processing.

Long-term outcomes after catheter ablation for idiopathic atypical atrial flutter

BackgroundIdiopathic atypical (non–cavotricuspid isthmus–dependent) atrial flutter (IAAFL) may be seen in patients without structural heart disease and without previous cardiac surgery or ablation. ObjectiveThis study sought to determine the patient characteristics, electrophysiologic and electroanatomic properties, and clinical outcomes after ablation in patients with IAAFL. MethodsWe retrospectively compared IAAFL patients with cavotricuspid isthmus–dependent AFL (C-AFL) patients undergoing catheter ablation. The primary outcome was a composite of death from cardiovascular causes, ischemic stroke, and hospitalization for worsening of heart failure. ResultsOf 180 patients who underwent catheter ablation for AFL, 89 were included in this study (22 IAAFL and 67 C-AFL). Electrophysiologic study showed significantly longer intra-atrial conduction time and lower atrial voltage during sinus rhythm in the IAAFL group compared with the C-AFL group. The atrial scar was observed in all 22 IAAFL patients, with the most common sites being the posterior or lateral wall of the right atrium in 10 (45.5%) and the anterior wall of the left atrium in 8 (36.4%). During 3.5 ± 2.8 years of follow-up, the composite primary end point occurred significantly more frequently in the IAAFL group (hazard ratio [HR], 3.45; 95% confidence interval [CI], 1.20–9.89; P = .015). In multivariable analysis, brain natriuretic peptide levels (HR, 1.01; 95% CI, 1.00–1.01, per 1 pg/mL; P = .01) and IAAFL (HR, 4.14; 95% CI, 1.21–14.07; P = .02) were independently associated with the primary outcome. ConclusionIAAFL in patients had distinct electrophysiologic features suggestive of atrial cardiomyopathy. These patients are at risk for development of cardiovascular adverse events after ablation.