Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents.

Voltage-gated sodium channels (Nav) are key players in excitable tissues with the capability to generate and propagate action potentials. Mutations in the genes encoding Navs can lead to severe inherited diseases, and some of these so-called channelopathies show temperature-sensitive phenotypes, for example, paramyotonia congenita, Brugada syndrome, febrile seizure syndromes, and inherited pain syndromes like erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). Nevertheless, most investigations of mutation-induced gating effects have been conducted at room temperature, and thus the role of cooling or warming in channelopathies remains poorly understood.

Corrigendum: Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor.

[This corrects the article DOI: 10.3389/fphar.2023.

Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor.

The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products, and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents.

Extracellular binding sites of positive and negative allosteric P2X4 receptor modulators.

Aims: P2X receptors are ATP-gated ion channels which play a role in many pathophysiological conditions. They are considered as novel drug targets, particularly in the fields of pain, (neuro) inflammation, and cancer. Due to difficulties in developing drug-like orthosteric ligands that bind to the highly polar ATP binding site, the design of positive and negative allosteric modulators (PAMs and NAMs) is a promising strategy.

BAC transgenic mice to study the expression of P2X2 and P2Y receptors.

Extracellular purines are important signaling molecules involved in numerous physiological and pathological processes via the activation of P2 receptors. Information about the spatial and temporal P2 receptor (P2R) expression and its regulation remains crucial for the understanding of the role of P2Rs in health and disease. To identify cells carrying P2X2Rs in situ, we have generated BAC transgenic mice that express the P2X2R subunits as fluorescent fusion protein (P2X2-TagRFP).

Uncoupling sodium channel dimers restores the phenotype of a pain-linked Na 1.7 channel mutation.

Background And Purpose: The voltage-gated sodium channel Na 1.7 is essential for adequate perception of painful stimuli. Mutations in the encoding gene, SCN9A, cause various pain syndromes in humans.

Dataset of electrophysiological patch-clamp recordings of the effect of the compounds deltamethrin, ATx-II and β4-peptide on human cardiac Nav1.5 sodium channel gating properties.

This article describes the effect of the pyrethroid insecticide deltamethrin on the cardiac voltage-gated sodium channel Nav1.5. Two concentrations of deltamethrin were used and the effects were compared with those of the sea anemone toxin ATx-II and β4-peptide, which is the C-terminus of the Nav channel β-subunit.

Mechanism underlying hooked resurgent-like tail currents induced by an insecticide in human cardiac Nav1.5.

Voltage-gated sodium channels are responsible not only for the fast upstroke of the action potential, but they also modify cellular excitability via persistent and resurgent currents. Insecticides act via permanently opening sodium channels to immobilize the animals. Cellular recordings performed decades ago revealed distinctly hooked tail currents induced by these compounds.

Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors.

The homotrimeric P2X3 receptor, one of the seven members of the ATP-gated P2X receptor family, plays a crucial role in sensory neurotransmission. P2X3 receptor antagonists have been identified as promising drugs to treat chronic cough and are suggested to offer pain relief in chronic pain such as neuropathic pain. Here, we analysed whether compounds affect P2X3 receptor activity by high-throughput screening of the Spectrum Collection of 2000 approved drugs, natural products and bioactive substances.

Bile acids are potent inhibitors of rat P2X2 receptors.

Extracellular adenosine triphosphate (ATP) regulates a broad variety of physiological functions in a number of tissues partly via ionotropic P2X receptors. Therefore, P2X receptors are promising targets for the development of therapeutically active molecules. Bile acids are cholesterol-derived amphiphilic molecules; their primary function is the facilitation of efficient nutrient fat digestion.

Author Correction: The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel.

The originally published version of this article contained an error in the name of the author Flóra Gölöncsér, which was incorrectly given as Flóra Göröncsér. This has now been corrected in both the PDF and HTML versions of the article.

Loss-of-function of Nav1.8/D1639N linked to human pain can be rescued by lidocaine.

Mutations in voltage-gated sodium channels are associated with altered pain perception in humans. Most of these mutations studied to date present with a direct and intuitive link between the altered electrophysiological function of the channel and the phenotype of the patient. In this study, we characterize a variant of Nav1.

Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism.

Haploinsufficiency of is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation.

The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel.

Two subclasses of acid-sensing ion channels (ASIC3) and of ATP-sensitive P2X receptors (P2X3Rs) show a partially overlapping expression in sensory neurons. Here we report that both recombinant and native receptors interact with each other in multiple ways. Current measurements with the patch-clamp technique prove that ASIC3 stimulation strongly inhibits the P2X3R current partly by a Ca-dependent mechanism.

Inverse correlation between vascular endothelial growth factor back-filtration and capillary filtration pressures.

Background: Vascular endothelial growth factor A (VEGF) is an essential growth factor during glomerular development and postnatal homeostasis. VEGF is secreted in high amounts by podocytes into the primary urine, back-filtered across the glomerular capillary wall to act on endothelial cells. So far it has been assumed that VEGF back-filtration is driven at a constant rate exclusively by diffusion.

The protective effect of resveratrol in the transmission of neuropathic pain mediated by the P2X receptor in the dorsal root ganglia.

The P2X receptor mediates afferent nerve activation and is related to chronic neuropathic pain. Resveratrol (RES) has also been reported to exhibit anti-inflammatory effects. In this study, we investigated the neuroprotective effect of RES on the transmission of neuropathic pain mediated by the P2X receptor.

Inter-subunit disulfide locking of the human P2X3 receptor elucidates ectodomain movements associated with channel gating.

P2X3 receptors (P2X3R) are trimeric ATP-gated cation channels involved in sensory neurotransmission and inflammatory pain. We used homology modeling and molecular dynamic simulations of the hP2X3R to identify inter-subunit interactions of residues that are instrumental to elucidate conformational changes associated with gating of the hPX3R. We identified an ionic interaction between E112 and R198 of the head domain and dorsal fin domain, respectively, and E57 and T263 of the lower body domains of adjacent subunits and detected a marked rearrangement of these domains during gating of the hP3X3R.

Flexible subunit stoichiometry of functional human P2X2/3 heteromeric receptors.

The aim of the present work was to clarify whether heterotrimeric P2X2/3 receptors have a fixed subunit stoichiometry consisting of one P2X2 and two P2X3 subunits as previously suggested, or a flexible stoichiometry containing also the inverse subunit composition. For this purpose we transfected HEK293 cells with P2X2 and P2X3 encoding cDNA at the ratios of 1:2 and 4:1, and analysed the biophysical and pharmacological properties of the generated receptors by means of the whole-cell patch-clamp technique. The concentration-response curves for the selective agonist α,β-meATP did not differ from each other under the two transfection ratios.

Key sites for P2X receptor function and multimerization: overview of mutagenesis studies on a structural basis.

P2X receptors constitute a seven-member family (P2X1-7) of extracellular ATP-gated cation channels of widespread expression. Because P2X receptors have been implicated in neurological, inflammatory and cardiovascular diseases, they constitute promising drug targets. Since the first P2X cDNA sequences became available in 1994, numerous site-directed mutagenesis studies have been conducted to disclose key sites of P2X receptor function and oligomerization.

A hydrophobic residue in position 15 of the rP2X3 receptor slows desensitization and reveals properties beneficial for pharmacological analysis and high-throughput screening.

The homotrimeric P2X3 subtype, one of the seven members of the ATP-gated P2X receptor family, plays a role in sensory neurotransmission, including nociception. To overcome the bias resulting from fast desensitization of the P2X3 receptor in dose-response analyses, a non-desensitizing P2X2-X3 receptor chimera has been repeatedly used as a surrogate for the P2X3 receptor for functional analysis. Here, we show that only three of the P2X2-specific amino acid residues of the P2X2-X3 chimera, (19)P(21)V(22)I, are needed to confer a slowly desensitizing phenotype to the P2X3 receptor.

Heteromeric assembly of P2X subunits.

Transcripts and/or proteins of P2X receptor (P2XR) subunits have been found in virtually all mammalian tissues. Generally more than one of the seven known P2X subunits have been identified in a given cell type. Six of the seven cloned P2X subunits can efficiently form functional homotrimeric ion channels in recombinant expression systems.