Ion Current Research Articles

Effects of aconitine on membrane currents and action potentials in neonatal rat ventricular myocytes and its impact on electrocardiographic changes

This study presents an analysis of the electrophysiological effects of aconitine, a toxic diterpenoid alkaloid derived from Aconitum plants, on neonatal rat ventricular myocytes (NRVMs). The research investigates the potential impact of aconitine on various ion currents and cardiac action potentials, shedding light on its arrhythmogenic properties. Whole-cell patch-clamp experiments were conducted to assess the effects of aconitine on delayed-rectifier K+ currents (IK(DR)) and inwardly rectifying K+ currents (IK(IR) in NRVMs. The findings indicate that aconitine exposure led to the inhibition of (IK(DR)) and (IK(IR)), suggesting its potential influence on cardiac repolarization and excitability. Notably, aconitine induced transient inward current (ITI) and early after-depolarizations (EADs) in a concentration- dependent manner, both of which have implications for cardiac arrhythmias. Moreover, the study examined the electrocardiogram changes in Sprague-Dawley rats upon aconitine injection, revealing a prolonged QT interval and the emergence of polymorphic ventricular tachycardia (VTs), indicative of arrhythmic effects. The study emphasizes the importance of understanding the electrophysiological impact of aconitine and similar compounds, considering their potential therapeutic applications and associated toxicities.

Theoretical calculations of the performance of Li7NbO6 and its doped Phases as solid electrolytes.

Materials with Hexagonal Close Packed (HCP) anionic configuration contain promising lithium-ion conductors. In the HCP anionic structure, when the non-lithium cations occupy the octahedral sites (the important diffusion channels for lithium ions), it is not known whether the nature of fast lithium-ion diffusion will be retained. This work systematically studied the lithium-ion diffusion properties of Li7NbO6 as well as its doped phases on the basis of first-principles calculations. The calculation results show that the lithium-ion conductivity of Li7NbO6 is 0.008 mS cm-1 at room temperature, while the doped phase Li55Nb7WO48 with W6+ doping at the Nb sites possesses a higher lithium-ion conductivity of 0.28 mS cm-1 at room temperature and an activation energy of 0.34 eV. The lithium-ion diffusion mechanism in Li7NbO6 and its doped phase involves concerted migration; besides, they are poor conductors of electrons regardless of whether doping is applied. In addition, W6+ doping increases the reduction limit of the electrochemical window due to its strong oxidizing property; therefore, an artificial SEI film needs to be applied to reduce interfacial decomposition. The discovery and characterization of the new fast lithium-ion conductor Li55Nb7WO48 provide theoretical guidance for the development of new solid electrolytes.

SnS2 nanoparticles embedded in sulfurized polyacrylonitrile composite fibers for high‐performance potassium‐ion batteries

AbstractPotassium‐ion batteries (PIBs) have garnered significant attention as a promising alternative to commercial lithium‐ion batteries (LIBs) due to abundant and cost‐efficient potassium reserves. However, the large size of potassium ions and the resulting sluggish reaction kinetics present major obstacles to the widespread use of PIBs. Herein, we present a simple method to ingeniously encapsulate SnS2 nanoparticles within sulfurized polyacrylonitrile (SPAN) fibers (SnS2@SPAN) for serving as a high‐performance PIB anode. The large interlayer spacing of SnS2 provides a fast transport channel for potassium ions during charge–discharge cycles, while the one‐dimensional SPAN skeleton offers massive binding sites and shortens the diffusion path for potassium ions, facilitating faster reaction kinetics. Additionally, the excellent ductility of SPAN can effectively accommodate the large volume changes that occur in SnS2 upon potassium‐ion insertion, thereby enhancing the cyclic stability of SnS2. Benefiting from the above advantages, the SnS2@SPAN composites exhibit impressive cyclability over 500 cycles at 4 A g−1, with a capacity retention rate close to 100%. This study provides an effective approach for stabilizing high‐capacity PIB anode materials with large volume variations.

A polymeric artificial solid electrolyte interface dramatically enhances lithium-ion transport.

Coulombic efficiency and cycle life require further improvement in an ever-growing practical demand for lithium-ion batteries (LIBs), which are one of the most prevalent electrochemical energy storage systems. In this work, a more stable and highly lithium-ion (Li-ion) conductive artificial solid electrolyte interface (A-SEI) is constructed by coating polythiophene (PTh) on the surface of a graphite anode based on molecular dynamic simulations. Our findings reveal that PTh chains effectively prevent direct contact between the electrolyte and the negative electrode while providing a rapid transport channel for lithium ions (Li-ions), resulting in significantly shorter trapping times for Li-ions-at least two orders of magnitude shorter than those in the predominant component of traditional SEI layers.

Notoginsenoside R1, a metabolite from Panax notoginseng (Burkill) F.H.Chen, stimulates insulin secretion through activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway.

For ages, botanical medicine has been used in the treatment of diabetes mellitus (DM). Notoginsenoside R1 (NGR1), a Panax notoginseng (Burkill) F.H.Chen metabolite, has been documented to possess antidiabetic action in vivo. However, its precise molecular mechanism of action is not clear. We evaluated NGR1's effects on blood glucose in vivo and then evaluated in vitro whether NGR1 has effects on insulin secretion and the probable molecular pathways involved in NGR1-induced insulin secretion. Diabetes was induced in mice by streptozotocin. Glucose tolerance test was performed before and after NGR1 was administered intraperitoneally to diabetic animals for 4 weeks. Static and perifusion experiments were performed using isolated female BALB/c mouse islets. Preproinsulin (Ins) mRNA expression was measured using q-PCR. Protein expression of PI3K/Akt pathway was assessed using the fully automated Wes™ capillary-based protein electrophoresis. Treatment of diabetic mice with NGR1 improved their glucose intolerance. In vitro, NGR1 increased insulin secretion in a concentration-dependent manner. NGR1 initiated the secretion of insulin at 2mM glucose and augmented glucose-stimulated insulin secretion which was sustained throughout NGR1 perifusion. NGR1-induced insulin secretion was not altered by a voltage gated calcium channel blocker or protein kinase A inhibitor. NGR1 did not significantly modulate Ins mRNA expression. However, NGR1 significantly increased the levels of phospho-Akt and phopho-p-85. In conclusion, this study has shown that NGR1 ameliorates hyperglycemia in diabetic mice. NGR1 has a direct insulin secretagogue activity on mouse islets, stimulates insulin secretion at both basal and postprandial glucose concentrations, and activates PI3K/Akt pathway to induce insulin secretion. These results suggest that NGR1 may provide an alternative therapy to manage DM.

Circadian rhythms in the Drosophila eye may regulate adaptation of vision to light intensity.

The sensitivity of the eye at night would lead to complete saturation of the eye during the day. Therefore, the sensitivity of the eye must be down-regulated during the day to maintain visual acuity. In the Drosophila eye, the opening of TRP and TRPL channels leads to an influx of Ca++ that triggers down-regulation of further responses to light, including the movement of the TRPL channel and Gα proteins out of signaling complexes found in actin-mediated microvillar extensions of the photoreceptor cells (the rhabdomere). The eye also exhibits a light entrained-circadian rhythm, and we have recently observed that one component of this rhythm (BDBT) becomes undetectable by antibodies after exposure to light even though immunoblot analyses still detect it in the eye. BDBT is necessary for normal circadian rhythms, and in several circadian and visual mutants this eye-specific oscillation of detection is lost. Many phototransduction signaling proteins (e.g., Rhodopsin, TRP channels and Gα) also become undetectable shortly after light exposure, most likely due to a light-induced compaction of the rhabdomeric microvilli. The circadian protein BDBT might be involved in light-induced changes in the rhabdomere, and if so this could indicate that circadian clocks contribute to the daily adaptations of the eye to light. Likewise, circadian oscillations of clock proteins are observed in photoreceptors of the mammalian eye and produce a circadian oscillation in the ERG. Disruption of circadian rhythms in the eyes of mammals causes neurodegeneration in the eye, demonstrating the importance of the rhythms for normal eye function.

MOF-modified dendrite-free gel polymer electrolyte for zinc-ion batteries.

Zinc-ion batteries are promising candidates for large-scale energy storage, and gel polymer electrolytes (GPEs) play an important role in zinc-ion battery applications. Metal-organic frameworks (MOFs) are characterized by large specific surface areas and ordered pores. This highly ordered microporous structure provides a continuous transport channel for ions, thus realizing the high-speed transmission of ions. In this paper, an MOF-modified dendrite-free GPE was designed. The incorporation of MOF particles not only reduces the crystallinity of the polymer, increases the motility of the molecular chains, and facilitates the transfer of Zn2+, but also attracts anions to reduce polarization during electrochemical reactions. It was shown that this MOF-modified gel polymer electrolyte has a higher ionic conductivity compared to other PVDF-based polymer electrolytes (approximate range of 2 × 10-4 to 3 × 10-3 S cm-1), with a very high conductivity (1.63 mS cm-1) even at -20 °C. The Zn/Zn symmetric cell could maintain operation for more than 3600 h at a current density of 1 mA cm-2, and SEM showed that the MOF-modified gel electrolyte had uniform Zn2+ deposition.

Utilizing solid-state nanopore sensing for high-efficiency and precise targeted localization in antiviral drug development.

The efficient identification and validation of drug targets are paramount in drug discovery and development. Excessive costs, intricate procedures, and laborious sample handling frequently encumber contemporary methodologies. In this study, we introduce an innovative approach for the expeditious screening of drug targets utilizing solid-state nanopores. These nanopores provide a label-free, ultra-sensitive, and high-resolution platform for the real-time detection of biomolecular interactions. By observing the changes in relative ion currents over time after mixing different peptides with small molecule drugs, and supplementing this with noise analysis, we can pinpoint specific regions of drug action, thereby enhancing both the speed and cost-efficiency of drug development. This research offers novel insights into drug discovery, expands current perspectives, and lays the groundwork for formulating effective therapeutic strategies across a spectrum of diseases.

Aromatic foldamer-derived transmembrane transporters.

This review is the first to focus on transmembrane transporters derived from aromatic foldamers, with most studies reported over the past decade. These foldamers have made significant strides in mimicking the essential functions of natural ion channel proteins. With their aromatic backbones rigidified by intramolecular hydrogen bonds or differential repulsive forces, this innovative family of molecules stands out for its structural diversity and functional adaptability. They achieve efficient and selective ion and molecule transport across lipid bilayers via carefully designed helical structures and tunable large cavities. Recent developments in this field highlight the transformative potential of foldamers in therapeutic applications and biomaterial engineering. Key advances include innovative molecular engineering strategies that enable highly selective ion transport by fine-tuning structural and functional attributes. Specific modifications to macrocyclic or helical foldamer structures have allowed precise control over ion selectivity and transport efficiency, with notable selectivity for K+, Li+, H+ and water molecules. Although challenges remain, future directions may focus on more innovative molecular designs, optimizing synthetic methods, improving membrane transport properties, integrating responsive designs that adapt to environmental stimuli, and fostering interdisciplinary collaborations. By emphasizing the pivotal role of aromatic foldamers in modern chemistry, this review aims to inspire further development, offering new molecular toolboxes and strategies to address technological and biological challenges in chemistry, biology, medicine, and materials science.

The diagnostic effectiveness of criteria for neuromyelitis optica spectrum disorders in the Russian clinical practice

To compare the diagnostic criteria of 2006 (DC 2006) and 2015 (DC 2015) in the Russian population of patients with suspected neuromyelitis optica spectrum disorders (NMOSD), with the calculation of their sensitivity, specificity, accuracy and predictive value. We reviewed medical records of suspected NMOSD patients who were therefore examined for the presence of serum autoantibodies targeting the aquaporin-4 water channel protein (AQP4-IgG) in 6 specialized Russian (Nizhny Novgorod and Moscow) medical centers. One hundred patients (78 female), aged 17 to 74 years (mean 38.1±13.3 years), were included. The follow-up period ranged from 4 to 108 months (mean 59.7±31.6 months). During the follow-up the diagnosis of NMOSD was confirmed in 32 people, and 68 patients had diagnoses different from NMOSD. At the disease onset, 68.8% of patients were seropositive for AQP4-IgG. The mean time for confirming NMOSD diagnosis was 15.2±14.2 months. At the disease onset, 36% of patients fulfilled the DC 2015, the diagnosis was subsequently confirmed in 77.8% out of them. 26% of the patients fulfilled the DC 2006, the diagnosis was subsequently confirmed in 84.6% out of them. The sensitivity of DC 2006/DC 2015 was 69%/88%, specificity 94%/88%, accuracy 86%/88%, negative predictive value 85%/94%, positive predictive value 86%/78%. The specificity, sensitivity and accuracy of modern diagnostic criteria for NMOSD In Russian patients is comparable to those obtained in foreign studies. DC 2015 helps to diagnose NMOSD earlier than DC 2006, but they have a lower specificity.

Bifidobacterium longum S3 alleviates loperamide-induced constipation by modulating intestinal acetic acid and stearic acid levels in mice.

Constipation is a major gastrointestinal (GI) symptom worldwide, with diverse causes of formation, and requires effective and safe therapeutic measures. In the present study, we used loperamide hydrochloride to establish a constipation model and assessed the effect of Bifidobacterium on constipation and its possible mechanism of relief. The results showed that B. longum S3 exerted a constipation-relieving effect primarily by improving the gut microbiota, enriching genera including Lactobacillus, Alistipes, and Ruminococcaceae UCG-007, and decreasing the bacteria Lachnospiraceae NK4B4 group. These changes may thereby increase acetic acid and stearic acid (C18:0) levels, which significantly increase the expression levels of ZO-1 and MUC-2, repair intestinal barrier damage and reduce inflammation (IL-6). Furthermore, it also inhibited oxidative stress levels (SOD and CAT), decreased the expression of water channel proteins (AQP4 and AQP8), significantly elevated the Gas, 5-HT, PGE2, and Ach levels, and reduced nNOS and VIP levels to improve the intestinal luminal transit time and fecal water content. Collectively, these changes resulted in the alleviation of constipation.

Exploring transmembrane allostery in the MexB: DB08385 variant as a promising inhibitor-like candidate against Pseudomonas aeruginosa antibiotic resistance: a computational study.

Pseudomonas aeruginosa, a formidable pathogen renowned for its antimicrobial resistance, poses a significant threat to immunocompromised individuals. In this regard, the MexAB-OprM efflux pump acts as a pivotal line of defense by extruding antimicrobials from bacterial cells. The inner membrane homotrimeric protein MexB captures antibiotics and translocates them into the outer membrane OprM channel protein connected through the MexA adaptor protein. Despite extensive efforts, competitive inhibitors targeting the tight (T) protomer of the MexB protein have not received FDA approval for medical use. Over the past few years, allosteric inhibitors have become popular as alternatives to the classical competitive inhibitor-based approach because of their higher specificity, lower dosage, and reduced toxicological effects. Hence, in this study, we unveiled the existence of a transmembrane allosteric binding pocket of MexB inspired by the recent discovery of an important allosteric inhibitor, BDM88855, for the homolog AcrB protein. While repurposing BDM88855 proved ineffective in controlling the MexB loose (L) protomer, our investigation identified a promising alternative: a chlorine-containing variant of DB08385 (2-Cl DB08385 or Variant 1). Molecular dynamics simulations, including binding free energy estimation coupled with heterogeneous dielectric implicit membrane model (implicit-membrane MM/PBSA), interaction entropy (IE) analysis and potential of mean force (PMF) calculation, demonstrated Variant 1's superior binding affinity to the transmembrane pocket, displaying the highest energy barrier in the ligand unbinding process. To elucidate the allosteric crosstalk between the transmembrane and porter domain of MexB, we employed the 'eigenvector centrality' measure in the linear mutual information obtained from the protein correlation network. Notably, this study confirmed the presence of an allosteric transmembrane site in the MexB L protomer. In addition to this, Variant 1 emerged as a potent regulator of allosteric crosstalk, inducing an 'O-L intermediate state' in the MexB L protomer. This induced state might hold the potential to diminish substrate intake into the access pocket, leading to the ineffective efflux of antibiotics.

Clinical phenotypes of developmental and epileptic encephalopathy-related recurrent KCNH5 missense variant p.R327H in Chinese children

KCNH5 gene encodes for the voltage-gated potassium channel protein Kv10.2. Here, we investigated the clinical features of developmental and epileptic encephalopathy (DEE) in five Chinese pediatric patients with a missense mutation (p.R327H) in KCNH5 gene. These patients had undergone video EEG to evaluate background features and epileptiform activity, as well as 3.0 T MRI scans for structural analysis and intelligence assessments using the Gesell Developmental Observation or Wechsler Intelligence Scale for Children. Seizure onset occurs between 4 and 10 months of age, with focal and generalized tonic-clonic seizures being common. Initial EEG findings showed multiple multifocal sharp waves, sharp slow waves or spike slow waves, and spike waves. Brain MRI revealed widened extracerebral space in only one patient. Mechanistically, the KCNH5 mutation disrupts the two hydrogen bonds between Arg327 and Asp304 residues, potentially altering the protein’s structural stability and function. Almost 80 % of patients receiving add-on valproic acid (VPA) therapy experienced a reduction in epileptic seizure frequency. Altogether, this study presents the first Chinese cohort of pediatric DEE patients with the KCNH5 p.R327H mutation, highlighting focal seizures as the predominant seizure type and incomplete mutation penetrance. Add-on VPA therapy was likely effective in the early stages of DEE pathogenesis.

Creating Computational Models of Ion Channel Dynamics.

Markov models are widely used to represent ion channel protein configurations as different states in the model's topology. Such models allow for dynamic simulation of ion channel kinetics through the simulated application of voltage potentials across a cell membrane. In this chapter, we present a general method for creating Markov models of ion channel kinetics using computational optimization alongside a fully featured example model of a cardiac potassium channel. Our methods cover designing training protocols, iteratively testing potential model topologies for structure identification, creation of algorithms for model simulation, as well as methods for assessing the quality of fit for a finalized model.

Comparative DNA methylation reveals epigenetic adaptation to high altitude in snub-nosed monkeys.

DNA methylation plays a crucial role in environmental adaptations. Here, using whole-genome bisulfite sequencing, we generated comprehensive genome-wide DNA methylation profiles for the high-altitude Yunnan snub-nosed monkey ( Rhinopithecus bieti) and the closely related golden snub-nosed monkey ( R. roxellana). Our findings indicated a slight increase in overall DNA methylation levels in golden snub-nosed monkeys compared to Yunnan snub-nosed monkeys, suggesting a higher prevalence of hypermethylated genomic regions in the former. Comparative genomic methylation analysis demonstrated that genes associated with differentially methylated regions were involved in membrane fusion, vesicular formation and trafficking, hemoglobin function, cell cycle regulation, and neuronal differentiation. These results suggest that the high-altitude-related epigenetic modifications are extensive, involving a complete adaptation process from the inhibition of single Ca 2+ channel proteins to multiple proteins collaboratively enhancing vesicular function or inhibiting cell differentiation and proliferation. Functional assays demonstrated that overexpression or down-regulation of candidate genes, such as SNX10, TIMELESS, and CACYBP, influenced cell viability under stress conditions. Overall, this research suggests that comparing DNA methylation across closely related species can identify novel candidate genomic regions and genes associated with local adaptations, thereby deepening our understanding of the mechanisms underlying environmental adaptations.

Synthetic cation channel: reconstructing the ion permeation pathway of TRPA1 in an artificial system.

A novel artificial cation channel was developed by rebuilding the ion permeation pathway of the natural channel protein (TRPA1) in a synthetic system. This tubular molecule can effectively embed into lipid bilayers and form transmembrane channels, thereby mediating cation transport. Furthermore, due to its carboxyl-modified ion permeation pathway, the transport activity of this artificial channel can be modulated by the pH of the buffer solution.

Dissection of Targeting Molecular Mechanisms of Celastrol-induced Nephrotoxicity via A Combined Deconvolution Strategy of Chemoproteomics and Metabolomics.

Celastrol (Cel), derived from the traditional herb Tripterygium wilfordii Hook. f., has anti-inflammatory, anti-tumor, and immunoregulatory activities. Renal dysfunction, including acute renal failure, has been reported in patients following the administration of Cel-relative medications. However, the functional mechanism of nephrotoxicity caused by Cel is unknown. This study featured combined use of activity-based protein profiling and metabolomics analysis to distinguish the targets of the nephrotoxic effects of Cel. Results suggest that Cel may bind directly to several critical enzymes participating in metabolism and mitochondrial functions. These enzymes include voltage-dependent anion-selective channel protein 1 (essential for maintaining mitochondrial configurational and functional stability), pyruvate carboxylase (involved in sugar isomerization and the tricarboxylic acid cycle), fatty acid synthase (related to β-oxidation of fatty acids), and pyruvate kinase M2 (associated with aerobic respiration). Proteomics and metabolomics analysis confirmed that Cel-targeted proteins disrupt some metabolic biosynthetic processes and promote mitochondrial dysfunction. Ultimately, Cel aggravated kidney cell apoptosis. These cumulative results deliver an insight into the potential mechanisms of Cel-caused nephrotoxicity. They may also facilitate development of antagonistic drugs to mitigate the harmful effects of Cel on the kidneys and improve its clinical applications.

Expression patterns of aquaporins 1, 3, 5 in canine mammary gland carcinomas.

Aquaporins (AQPs) are water channel proteins, and the expression of AQPs in carcinoma cells has received much attention over the last 15 years. In the veterinary field, however, little is known about the expression of AQPs. In the present study using immunohistochemistry, we examined the expression of AQP1, AQP3, and AQP5 in canine mammary gland carcinomas. The 27 samples comprised 10 grade I, 12 grade II, and 5 grade III samples (See Materials and Methods section for grade classification method). AQP1 was expressed in only 2 of the grade III carcinomas, and the expression was limited to spindle-shaped cells in the solid structure and on the outside of the solid mass. AQP3-positive cells were observed in 20 of 22 grade I and II samples. On the other hand, among grade III carcinomas, AQP3 was expressed only in spindle-shaped cells in 1 sample. AQP5 was expressed in all grade I and II carcinomas but not in the grade III tumors. In addition, enhanced expression of basolateral AQP3 and apical AQP5 was observed in lobular hyperplastic cells. These results suggest that the expression patterns of AQP3 and AQP5 can be of help for judging the grading of canine mammary tumors and that AQP1 is likely to be involved in metastasis. Moreover, AQP3 and AQP5 might be relevant to lactation in female dogs.

Determination of the Immunomodulatory Role of OTOP2 in Colon Adenocarcinoma.

Background: Otopetrin 2 (OTOP2) is a conserved ion channel protein that regulates cell signaling, growth, and development. Although the role of OTOP2 in tumor suppression has been reported in several studies of colon adenocarcinoma (COAD), characterized its immunomodulatory effects on tumors. Methods: We conducted a thorough analysis of OTOP2 expression and its association with clinicopathological characteristics, immune-related pathways, and immune-related molecules in individuals with COAD using data from The Cancer Genome Atlas (TCGA) and confirmed the findings with tissue microarrays (TMAs). We conducted in vitro assays to demonstrate the tumor suppressive effect of OTOP2 in COAD cells. Results: OTOP2 expression was abnormal in multiple types of tumors and was significantly downregulated in patients with COAD (P<0.001). Moreover, the presence of OTOP2 was linked to enhanced survival in individuals diagnosed with COAD. In vitro experiments showed that OTOP2 suppressed cell proliferation, migration, invasion, and adhesion. Gene set enrichment analysis of the TCGA database indicated that OTOP2 was positively correlated with antigen presentation pathways and T cell responses. The immunophenoscore (IPS) indicated a positive correlation between OTOP2 expression and MHC molecule expression (P<0.001) as well as between OTOP2 expression and the number of effector cells (P<0.01). Immunohistochemical analysis of the TMAs revealed strong associations between OTOP2 expression and MHC-I, TAP1, and TAP2 expression, and between OTOP2 expression and CD8+ T cell infiltration in COAD patients. Conclusion: In summary, our research emphasizes the role of OTOP2 as a tumor suppressor, suggesting its use as a prognostic indicator and predictor of response to immunotherapy in COAD patients.

Human Transient Receptor Potential Ankyrin 1 Channel: Structure, Function, and Physiology.

The transient receptor potential ion channel TRPA1 is a Ca2+-permeable nonselective cation channel widely expressed in sensory neurons, but also in many nonneuronal tissues typically possessing barrier functions, such as the skin, joint synoviocytes, cornea, and the respiratory and intestinal tracts. Here, the primary role of TRPA1 is to detect potential danger stimuli that may threaten the tissue homeostasis and the health of the organism. The ability to directly recognize signals of different modalities, including chemical irritants, extreme temperatures, or osmotic changes resides in the characteristic properties of the ion channel protein complex. Recent advances in cryo-electron microscopy have provided an important framework for understanding the molecular basis of TRPA1 function and have suggested novel directions in the search for its pharmacological regulation. This chapter summarizes the current knowledge of human TRPA1 from a structural and functional perspective and discusses the complex allosteric mechanisms of activation and modulation that play important roles under physiological or pathophysiological conditions. In this context, major challenges for future research on TRPA1 are outlined.