TRPV2: a universal regulator in cellular physiology with a yet poorly defined thermosensitivity.

Transient receptor potential (TRP) ion channels serve as sensors for variations in ambient temperature, modulating both thermoregulation and temperature responsive cellular processes. Among these, the vanilloid TRP subfamily (TRPV) comprises six members and at least four of these members (TRPV1-TRPV4) have been associated with thermal sensation. TRPV2 has been described as a sensor for noxious heat, but subsequent studies have unveiled a more complex role for TRPV2 beyond temperature perception.

Protein-free media for cardiac differentiation of hPSCs in 2000 mL suspension culture.

Background: Commonly used media for the differentiation of human pluripotent stem cells into cardiomyocytes (hPSC-CMs) contain high concentrations of proteins, in particular albumin, which is prone to quality variations and presents a substantial cost factor, hampering the clinical translation of in vitro-generated cardiomyocytes for heart repair. To overcome these limitations, we have developed chemically defined, entirely protein-free media based on RPMI, supplemented with L-ascorbic acid 2-phosphate (AA-2P) and either the non-ionic surfactant Pluronic F-68 or a specific polyvinyl alcohol (PVA).

Methods And Results: Both media compositions enable the efficient, directed differentiation of embryonic and induced hPSCs, matching the cell yields and cardiomyocyte purity ranging from 85 to 99% achieved with the widely used protein-based CDM3 medium.

A Possible Role of Tetrodotoxin-Sensitive Na Channels for Oxidation-Induced Late Na Currents in Cardiomyocytes.

An accumulation of reactive oxygen species (ROS) in cardiomyocytes can induce pro-arrhythmogenic late Na currents by removing the inactivation of voltage-gated Na channels including the tetrodotoxin (TTX)-resistant cardiac α-subunit Nav1.5 as well as TTX-sensitive α-subunits like Nav1.2 and Nav1.

Transient stabilization of human cardiovascular progenitor cells from human pluripotent stem cells in vitro reflects stage-specific heart development in vivo.

Aims: Understanding the molecular identity of human pluripotent stem cell (hPSC)-derived cardiac progenitors and mechanisms controlling their proliferation and differentiation is valuable for developmental biology and regenerative medicine.

Methods And Results: Here, we show that chemical modulation of histone acetyl transferases (by IQ-1) and WNT (by CHIR99021) synergistically enables the transient and reversible block of directed cardiac differentiation progression on hPSCs. The resulting stabilized cardiovascular progenitors (SCPs) are characterized by ISL1pos/KI-67pos/NKX2-5neg expression.

The dynamic TRPV2 ion channel proximity proteome reveals functional links of calcium flux with cellular adhesion factors NCAM and L1CAM in neurite outgrowth.

TRPV2 voltage-insensitive, calcium-permeable ion channels play important roles in cancer progression, immune response, and neuronal development. Despite TRPV2's physiological impact, underlying endogenous proteins mediating TRPV2 responses and affected signaling pathways remain elusive. Using quantitative peroxidase-catalyzed (APEX2) proximity proteomics we uncover dynamic changes in the TRPV2-proximal proteome and identify calcium signaling and cell adhesion factors recruited to the molecular channel neighborhood in response to activation.

Functional and structural insights into activation of TRPV2 by weak acids.

Transient receptor potential (TRP) ion channels are involved in the surveillance or regulation of the acid-base balance. Here, we demonstrate that weak carbonic acids, including acetic acid, lactic acid, and CO activate and sensitize TRPV2 through a mechanism requiring permeation through the cell membrane. TRPV2 channels in cell-free inside-out patches maintain weak acid-sensitivity, but protons applied on either side of the membrane do not induce channel activation or sensitization.

[Opioid-free anesthesia : Wrong track or meaningful exit from the era of opioid-based analgesia?].

The limitations and disadvantages of opioids in anesthesia are very well known but the advantages combined with a lack of effective alternatives even now still prevents refraining from using opioids as part of an adequate pain therapy. For decades, pain research has had the declared goal of replacing opioids with new substances which have no serious side effects; however, currently this goal seems to be a long way off. Due to the media coverage of the "opioid crisis" in North America, the use of opioids for pain management is also increasingly being questioned by the patients.

Molecular details of ruthenium red pore block in TRPV channels.

Transient receptor potential vanilloid (TRPV) channels play a critical role in calcium homeostasis, pain sensation, immunological response, and cancer progression. TRPV channels are blocked by ruthenium red (RR), a universal pore blocker for a wide array of cation channels. Here we use cryo-electron microscopy to reveal the molecular details of RR block in TRPV2 and TRPV5, members of the two TRPV subfamilies.

Free heme and hemopexin in acute kidney injury after cardiopulmonary bypass and transient renal ischemia.

Free heme is released from hemoproteins during hemolysis or ischemia reperfusion injury and can be pro-inflammatory. Most studies on nephrotoxicity of hemolysis-derived proteins focus on free hemoglobin (fHb) with heme as a prosthetic group. Measurement of heme in its free, non-protein bound, form is challenging and not commonly used in clinical routine diagnostics.

Comparison of methylation estimates obtained via MinION nanopore sequencing and sanger bisulfite sequencing in the TRPA1 promoter region.

Background: Bisulfite sequencing has long been considered the gold standard for measuring DNA methylation at single CpG resolution. However, in recent years several new approaches like nanopore sequencing have been developed due to hints for a partial error-proneness of bisulfite sequencing. Since these errors were shown to be sequence-specific, we aimed to verify the methylation data of a particular region of the TRPA1 promoter from our previous studies obtained by bisulfite sequencing.

[Does medicinal cannabis or cannabis consumption have an influence on the perioperative anesthesiological management?].

The greatly increasing use of medicinal cannabis products as well as the upcoming legalization of cannabis not only require a general re-evaluation of how these substances might be classified as illegal drugs, but also enforce a critical view on the possible consequences that cannabis consumption might have on the anesthesiological strategies applied for surgical procedures. Although high-quality clinical studies are still lacking, several clinical studies meanwhile indicate that an active preoperative cannabis consumption seems to be associated with relevant pathophysiological aspects. Patients who regularly consume high doses of cannabis show an increased risk of cardiovascular and respiratory complications as well as the postoperative nausea and vomitting (PONV) associated with anesthesia.

Pain-causing stinging nettle toxins target TMEM233 to modulate Na1.7 function.

Voltage-gated sodium (Na) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived Na channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at Na channels, and that co-expression of TMEM233 modulates the gating properties of Na1.

Local Anesthetic Like Inhibition of the Cardiac Na Channel Nav1.5 by Chloroquine and Hydroxychloroquine.

Introduction: Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ) are successfully deployed for different diseases beyond the prophylaxis and treatment of malaria. Both substances exhibit antiviral properties and have been proposed for prophylaxis and treatment of COVID-19 caused by SARS-CoV-2. CQ and HCQ cause similar adverse events including life-threatening cardiac arrhythmia generally based on QT-prolongation, which is one of the most reported adverse events for both agents associated with the treatment of COVID-19.

Cell-Free Hemoglobin in Acute Kidney Injury after Lung Transplantation and Experimental Renal Ischemia/Reperfusion.

Cell-free hemoglobin (CFH), a pro-oxidant and cytotoxic compound that is released in hemolysis, has been associated with nephrotoxicity. Lung transplantation (LuTx) is a clinical condition with a high incidence of acute kidney injury (AKI). In this study, we investigated the plasma levels of CFH and haptoglobin, a CFH-binding serum protein, in prospectively enrolled LuTx patients ( = 20) with and without AKI.

The coumarin osthole is a non-electrophilic agonist of TRPA1.

The naturally occurring coumarin osthole has antipruritic properties, and recent reports suggest that this effect is due an inhibition or desensitization of the cation channels TRPV1 and TRPV3. Osthole was also suggested to activate TRPA1, an effect that should rather be pruritic than antipruritic. Here we characterized the effects of osthole on TRPA1 by means of ratiometric calcium imaging and patch clamp electrophysiology.

Antidepressants Are Poor Inhibitors of Heat-Evoked Ion Currents Mediated by TRPM2.

Introduction: The heat and redox-sensitive ion channel TRPM2 was reported to be a causative mechanism for depression in a mouse model and to be upregulated in the hippocampus in patients suffering from depressive disorders. TRPM2 may thus be a novel target for antidepressants, but so far, selective TRPM2-inhibitors have not yet been developed. In this in vitro study, we examined the inhibitory effects of several established antidepressants on heat-evoked inward currents of TRPM2.

Structural insights into TRPV2 activation by small molecules.

Transient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2.

The antipyretic effectiveness of dipyrone in the intensive care unit: A retrospective cohort study.

Introduction: Dipyrone (metamizol) is regularly used in critical care for pain and fever treatment, especially in Germany and Spain. However, indication for antipyretic therapy in critically ill patients is currently unclear and data for both the risk and benefit of dipyrone treatment in the intensive care environment are scarce. We hypothesized that antipyretic efficiency of dipyrone would not exceed antipyretic efficiency of acetaminophen.

Kidney injury after lung transplantation: Long-term mortality predicted by post-operative day-7 serum creatinine and few clinical factors.

Background: Acute kidney injury (AKI) after lung transplantation (LuTx) is associated with increased long-term mortality. In this prospective observational study, commonly used AKI-definitions were examined regarding prediction of long-term mortality and compared to simple use of the serum creatinine value at day 7 for patients who did not receive hemodialysis, and serum creatinine value immediately before initiation of hemodialysis (d7/preHD-sCr).

Methods: 185 patients with LuTx were prospectively enrolled from 2013-2014 at our center.

Effectiveness of amiodarone versus digitalis for heart rate control in critically ill patients with new-onset atrial fibrillation.

New-onset of atrial fibrillation (NOAF) in critically ill patients is the most common acute cardiac dysrhythmia, but evidence-based data regarding treatment strategies are scarce. In this retrospective monocentric study, we compared effectiveness of amiodarone versus digitalis for heart rate control in critically ill patients with new-onset of atrial fibrillation. We identified a total of 209 patients for the main analysis.

Distinct Mechanisms Account for In Vitro Activation and Sensitization of TRPV1 by the Porphyrin Hemin.

TRPV1 mediates pain occurring during sickling episodes in sickle cell disease (SCD). We examined if hemin, a porphyrin released during intravascular hemolysis modulates TRPV1. Calcium imaging and patch clamp were employed to examine effects of hemin on mouse dorsal root ganglion (DRG) neurons and HEK293t cells expressing TRPV1 and TRPA1.

Generation of hiPSC-derived low threshold mechanoreceptors containing axonal termini resembling bulbous sensory nerve endings and expressing Piezo1 and Piezo2.

Somatosensory low threshold mechanoreceptors (LTMRs) sense innocuous mechanical forces, largely through specialized axon termini termed sensory nerve endings, where the mechanotransduction process initiates upon activation of mechanotransducers. In humans, a subset of sensory nerve endings is enlarged, forming bulb-like expansions, termed bulbous nerve endings. There is no in vitro human model to study these neuronal endings.

A Novel SCN5A Variant Causes Temperature-Sensitive Loss Of Function in a Family with Symptomatic Brugada Syndrome, Cardiac Conduction Disease, and Sick Sinus Syndrome.

Introduction: Brugada syndrome (BrS) is an inherited arrhythmia syndrome associated with an increased risk of sudden cardiac death. SCN5A is the most important disease-modifying gene for BrS, but many SCN5A variants have not been functionally characterized. Furthermore, the temperature dependency of SCN5A is only rarely explored in in vitro analyses.