Conditional deletion of TRPC1 channel modulates synaptic plasticity, long term depression, and memory extinction in Fragile X syndrome mice.

Group I metabotropic glutamate receptors (mGluRs), particularly mGluR5, regulate synaptic plasticity via long-term depression (mGluR-LTD), a process implicated in declarative memory. We previously identified TRPC1, a highly expressed hippocampal ion channel, as a key mGluR5 effector. Using a Cre-tamoxifen system, we acutely deleted in a Fragile X syndrome (FXS) mouse model, characterized by mGluR5 hyperactivity, enhanced mGluR-LTD, and social deficits.

Hunting for lubeluzole analogues as antimyotonic agents with reduced cardiac liability.

Lubeluzole is a neuroprotective agent displaying antimyotonic activity. Lubeluzole clinical development as an antiischemic drug was discontinued due to a lack of efficacy in human trials and possible cardiac toxicity. Since lubeluzole is a potent inhibitor of the hERG channel, involved in long QT syndromes and the potentially fatal cardiac arrhythmia Torsade de Pointes, a series of lubeluzole analogues were prepared to investigate the structural requirements to reduce the affinity for hERG channels to possibly obtain safe antimyotonic drugs.

Primary Cell Cultures in Neurobiology: Optimized Protocol for Culture of Mouse Fetal Hindbrain Neurons.

Primary cultures of neural cells are important key tools for basic and translational neuroscience research. These primary cell cultures are classically generated from the rodent brain hippocampus or cortex and optimized for enrichment in neurons at the expense of glial cells. Importantly, considerable differences exist in neuronal cell populations and in glial cell contribution between different brain regions.

hERG stereoselective modulation by mexiletine-derived ureas: Molecular docking study, synthesis, and biological evaluation.

Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life-threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether-à-go-go-related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine-derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity.

Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory.

The postsynaptic inhibition through GABA receptors (GABAR) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K-Cl cotransporter KCC2 which extrudes Cl from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer's disease.

Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines.

Osteosarcoma is a heterogeneous tumor intimately linked to its microenvironment, which promotes its growth and spread. It is generally accompanied by cancer-induced bone pain (CIBP), whose main component is neuropathic pain. The TRPA1 ion channel plays a key role in metastasis and is increasingly expressed in bone cancer.

A TRPM7 mutation linked to familial trigeminal neuralgia: Omega current and hyperexcitability of trigeminal ganglion neurons.

Trigeminal neuralgia (TN) is a unique pain disorder characterized by intense paroxysmal facial pain within areas innervated by the trigeminal nerve. Although most cases of TN are sporadic, familial clusters of TN suggest that genetic factors may contribute to this disorder. Whole-exome sequencing in patients with TN reporting positive family history demonstrated a spectrum of variants of ion channels including TRP channels.

Prdm12 modulates pain-related behavior by remodeling gene expression in mature nociceptors.

Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors.

Overexpression of wild-type human amyloid precursor protein alters GABAergic transmission.

The function of the amyloid precursor protein (APP) is not fully understood, but its cleavage product amyloid beta (Aβ) together with neurofibrillary tangles constitute the hallmarks of Alzheimer's disease (AD). Yet, imbalance of excitatory and inhibitory neurotransmission accompanied by loss of synaptic functions, has been reported much earlier and independent of any detectable pathological markers. Recently, soluble APP fragments have been shown to bind to presynaptic GABA receptors (GABARs), subsequently decreasing the probability of neurotransmitter release.

Trigeminal Neuralgia TRPM8 Mutation: Enhanced Activation, Basal [Ca] and Menthol Response.

Objective: To assess the functional effects of a variant, c.89 G > A (p.Arg30Gln), in the transient receptor potential melastatin 8 (TRPM8) cold-sensing, nonselective cation channel, which we have previously identified in a patient with familial trigeminal neuralgia.

Mechanical activation of TRPV4 channels controls albumin reabsorption by proximal tubule cells.

Defects in protein reabsorption by the proximal tubule are toxic for epithelial cells in the nephron and may result in nephropathy. In this study, we showed that the ion channel TRPV4 modulated the endocytosis of albumin and low-molecular weight proteins in the proximal tubule. TRPV4 was found at the basolateral side of proximal tubule cells, and its mechanical activation by cell stretching induced Ca entry into the cytosol, which promoted endocytosis.

Correction: Gualdani, R.; et al. Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma. 2019, , 430.

The authors wish to make the following corrections to this paper [...

How TRPC Channels Modulate Hippocampal Function.

Transient receptor potential canonical (TRPC) proteins constitute a group of receptor-operated calcium-permeable nonselective cationic membrane channels of the TRP superfamily. They are largely expressed in the hippocampus and are able to modulate neuronal functions. Accordingly, they have been involved in different hippocampal functions such as learning processes and different types of memories, as well as hippocampal dysfunctions such as seizures.

Amyloid Precursor Protein (APP) Controls the Expression of the Transcriptional Activator Neuronal PAS Domain Protein 4 (NPAS4) and Synaptic GABA Release.

The amyloid precursor protein (APP) has been extensively studied as the precursor of the β-amyloid (Aβ) peptide, the major component of the senile plaques found in the brain of Alzheimer's disease (AD) patients. However, the function of APP per se in neuronal physiology remains to be fully elucidated. APP is expressed at high levels in the brain.

Role of the TRPC1 Channel in Hippocampal Long-Term Depression and in Spatial Memory Extinction.

Group I metabotropic glutamate receptors (mGluR) are involved in various forms of synaptic plasticity that are believed to underlie declarative memory. We previously showed that mGluR5 specifically activates channels containing TRPC1, an isoform of the canonical family of Transient Receptor Potential channels highly expressed in the CA1-3 regions of the hippocampus. Using a tamoxifen-inducible conditional knockout model, we show here that the acute deletion of the gene alters the extinction of spatial reference memory.

Human ether-à-go-go-related potassium channel: exploring SAR to improve drug design.

hERG is best known as a primary anti-target, the inhibition of which is responsible for serious side effects. A renewed interest in hERG as a desired target, especially in oncology, was sparked because of its role in cellular proliferation and apoptosis. In this study, we survey the most recent advances regarding hERG by focusing on SAR in the attempt to elucidate, at a molecular level, off-target and on-target actions of potential hERG binders, which are highly promiscuous and largely varying in structure.

Superparamagnetic iron oxide nanoparticles (SPIONs) modulate hERG ion channel activity.

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used in various biomedical applications, such as diagnostic agents in magnetic resonance imaging (MRI), for drug delivery vehicles and in hyperthermia treatment of tumors. Although the potential benefits of SPIONs are considerable, there is a distinct need to identify any potential cellular damage associated with their use. Since human ether à go-go-related gene (hERG) channel, a protein involved in the repolarization phase of cardiac action potential, is considered one of the main targets in the drug discovery process, we decided to evaluate the effects of SPIONs on hERG channel activity and to determine whether the oxidation state, the dimensions and the coating of nanoparticles (NPs) can influence the interaction with hERG channel.

Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma.

Cisplatin (CDDP) is one of the principal chemotherapeutic agents used for the first-line treatment of many malignancies, including non-small cell lung carcinoma (NSCLC). Despite its use for over 40 years, its mechanism of action is not yet fully understood. Store-operated calcium entry (SOCE), the main pathway allowing Ca entry in non-excitable cells, is involved in tumorogenesis, cancer progression and chemoresistance.

Activation of TRPC1 Channel by Metabotropic Glutamate Receptor mGluR5 Modulates Synaptic Plasticity and Spatial Working Memory.

Group I metabotropic glutamate receptors, in particular mGluR5, have been implicated in various forms of synaptic plasticity that are believed to underlie declarative memory. We observed that mGluR5 specifically activated a channel containing TRPC1, an isoform of the canonical family of transient receptor potential (TRPC) channels highly expressed in CA1-3 regions of the hippocampus. TRPC1 is able to form tetrameric complexes with TRPC4 and/or TRPC5 isoforms.

Drug Interactions With the Ca-ATPase From Sarco(Endo)Plasmic Reticulum (SERCA).

The sarco(endo)plasmic reticulum Ca-ATPase (SERCA) is an intracellular membrane transporter that utilizes the free energy provided by ATP hydrolysis for active transport of Ca ions from the cytoplasm to the lumen of sarco(endo)plasmic reticulum. SERCA plays a fundamental role for cell calcium homeostasis and signaling in muscle cells and also in cells of other tissues. Because of its prominent role in many physiological processes, SERCA dysfunction is associated to diseases displaying various degrees of severity.

Molecular Insights into hERG Potassium Channel Blockade by Lubeluzole.

Background/aims: Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in preclinical models of ischemic stroke. However, clinical research on lubeluzole is now at a standstill, since lubeluzole seems to be associated with the acquired long QT syndrome and ventricular arrhythmias. Since the cardiac cellular effects of lubeluzole have not been described thus far, an explanation for the lubeluzole-induced QT interval prolongation is lacking.

Lipoyl-Homotaurine Derivative (ADM_12) Reverts Oxaliplatin-Induced Neuropathy and Reduces Cancer Cells Malignancy by Inhibiting Carbonic Anhydrase IX (CAIX).

Oxaliplatin (OXA) is a valuable and largely used cancer drug which induces a serious and intractable neuropathy. The lipoyl-homotaurine derivative (ADM_12) reverts in vivo OXA-induced neuropathy, and it is an effective antagonist of the nociceptive sensor channel TRPA1. Unprecedentedly, this safe analgesic showed a synergy with OXA in vitro and proved to inhibit CA IX, a relevant therapeutic target, clearly interfering with pancreatic cancer cells' aggressiveness.