Acidification of rat TRPV1 alters the kinetics of capsaicin responses

TRPV1 (vanilloid receptor 1) receptors are activated by a variety of ligands such as capsaicin, as well as by acidic conditions and temperatures above 42°C. These activators can enhance the potency of one another, shifting the activation curve for TRPV1 to the left. In this study, for example, we observed an approximately 10-fold shift in the capsaicin EC(50 )(640 nM to 45 nM) for rat TRPV1 receptors expressed in HEK-293 cells when the pH was lowered from 7.4 to 5.5. To investigate potential causes for this shift in capsaicin potency, the rates of current activation and deactivation of whole-cell currents were measured in individual cells exposed to treatments of pH 5.5, 1 μM capsaicin or in combination. Acidic pH was found to both increase the activation rate and decrease the deactivation rate of capsaicin-activated currents providing a possible mechanism for the enhanced potency of capsaicin under acidic conditions. Utilizing a paired-pulse protocol, acidic pH slowed the capsaicin deactivation rate and was readily reversible. Moreover, the effect could occur under modestly acidic conditions (pH 6.5) that did not directly activate TRPV1. When TRPV1 was maximally activated by capsaicin and acidic pH, the apparent affinity of the novel and selective capsaicin-site competitive TRPV1 antagonist, A-425619, was reduced ~35 fold. This shift was overcome by reducing the capsaicin concentration co-applied with acidic pH. Since inflammation is associated with tissue acidosis, these findings enhance understanding of TRPV1 receptor responses in inflammatory pain where tissue acidosis is prevalent

Symmetric Instantons and Skyrme Fields

By explicit construction of the ADHM data, we prove the existence of a charge seven instanton with icosahedral symmetry. By computing the holonomy of this instanton we obtain a Skyrme field which approximates the minimal energy charge seven Skyrmion. We also present a one parameter family of tetrahedrally symmetric instantons whose holonomy gives a family of Skyrme fields which models a Skyrmion scattering process, where seven well-separated Skyrmions collide to form the icosahedrally symmetric Skyrmion.Comment: 22 pages plus 1 figure in GIF forma

Monosodium iodoacetate-induced joint pain is associated with increased phosphorylation of mitogen activated protein kinases in the rat spinal cord

<p>Abstract</p> <p>Background</p> <p>Intra-articular injection of monosodium iodoacetate (MIA) in the knee joint of rats disrupts chondrocyte metabolism resulting in cartilage degeneration and subsequent nociceptive behavior that has been described as a model of osteoarthritis (OA) pain. Central sensitization through activation of mitogen activated protein kinases (MAPKs) is recognized as a pathogenic mechanism in chronic pain. In the present studies, induction of central sensitization as indicated by spinal dorsal horn MAPK activation, specifically ERK and p38 phosphorylation, was assessed in the MIA-OA model.</p> <p>Results</p> <p>Behaviorally, MIA-injected rats displayed reduced hind limb grip force 1, 2, and 3 weeks post-MIA treatment. In the same animals, activation of phospho ERK1/2 was gradually increased, reaching a significant level at post injection week 3. Conversely, phosphorylation of p38 MAPK was enhanced maximally at post injection week 1 and decreased, but remained elevated, thereafter. Double labeling from 3-wk MIA rats demonstrated spinal pERK1/2 expression in neurons, but not glia. In contrast, p-p38 was expressed by microglia and a subpopulation of neurons, but not astrocytes. Additionally, there was increased ipsilateral expression of microglia, but not astrocytes, in 3-wk MIA-OA rats. Consistent with increased MAPK immunoreactivity in the contralateral dorsal horn, mechanical allodynia to the contralateral hind-limb was observed 3-wk following MIA. Finally, intrathecal injection of the MEK1 inhibitor PD98059 blocked both reduced hind-limb grip force and pERK1/2 induction in MIA-OA rats.</p> <p>Conclusion</p> <p>Results of these studies support the role of MAPK activation in the progression and maintenance of central sensitization in the MIA-OA experimental pain model.</p

P2X receptors in GtoPdb v.2023.1

P2X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2X Receptors [49, 146]) have a trimeric topology [118, 128, 144, 197] with two putative TM domains per P2X subunit, gating primarily Na+, K+ and Ca2+, exceptionally Cl-. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial basis for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single trimeric assembly in order to activate it [118, 144, 95, 103, 177]. Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers (e.g. P2X2:P2X3 in the nodose ganglion [280], P2X1:P2X5 in mouse cortical astrocytes [162], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [53, 234]. P2X2, P2X4 and P2X7 receptor activation can lead to influx of large cationic molecules, such as NMDG+, Yo-Pro, ethidium or propidium iodide [211]. The permeability of the P2X7 receptor is modulated by the amount of cholesterol in the plasma membrane [193]. The hemi-channel pannexin-1 was initially implicated in the action of P2X7 [212], but not P2X2, receptors [41], but this interpretation is probably misleading [215]. Convincing evidence now supports the view that the activated P2X7 receptor is immediately permeable to large cationic molecules, but influx proceeds at a much slower pace than that of the small cations Na+, K+, and Ca2+ [66]

P2X receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

P2X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2X Receptors [46, 134]) have a trimeric topology [118, 132, 177] with two putative TM domains, gating primarily Na+, K+ and Ca2+, exceptionally Cl-. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial criteria for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single receptor in order to activate it [132, 88, 96, 161]. Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers (e.g. P2X2:P2X3 in the nodose ganglion [251], P2X1:P2X5 in mouse cortical astrocytes [146], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [50, 207]. P2X2, P2X4 and P2X7 receptors have been shown to form functional homopolymers which, in turn, activate pores permeable to low molecular weight solutes [229]. The hemi-channel pannexin-1 has been implicated in the pore formation induced by P2X7 [188], but not P2X2 [38], receptor activation

P2X receptors (version 2020.4) in the IUPHAR/BPS Guide to Pharmacology Database

P2X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2X Receptors [48, 141]) have a trimeric topology [124, 139, 188] with two putative TM domains, gating primarily Na+, K+ and Ca2+, exceptionally Cl-. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial criteria for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single receptor in order to activate it [139, 93, 101, 170]. Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers (e.g. P2X2:P2X3 in the nodose ganglion [265], P2X1:P2X5 in mouse cortical astrocytes [155], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [52, 221]. P2X2, P2X4 and P2X7 receptor activation can also lead to influx of large cationic molecules, such as NMDG, Yo-Pro, ethidium or propidium iodide [200]. The hemi-channel pannexin-1 was initially implicated in the action of P2X7 [201], but not P2X2, receptors [40], but this interpretation is probably misleading. Convincing evidence now supports the view that the activated P2X7 receptor is immediately permeable to large cationic molecules, but influx proceeds at a much slower pace than that of the small cations Na+, K+, and Ca2+ [64]

Rare Genetic Variation in 135 Families With Family History Suggestive of X-Linked Intellectual Disability.

Families with multiple male children with intellectual disability (ID) are usually suspected of having disease due to a X-linked mode of inheritance and genetic studies focus on analysis of segregating variants in X-linked genes. However, the genetic cause of ID remains elusive in approximately 50% of affected individuals. Here, we report the analysis of next-generation sequencing data in 274 affected individuals from 135 families with a family history suggestive of X-linked ID. Genetic diagnoses were obtained for 19% (25/135) of the families, and 24% (33/135) had a variant of uncertain significance. In 12% of cases (16/135), the variants were not shared within the family, suggesting genetic heterogeneity and phenocopies are frequent. Of all the families with reportable variants (43%, 58/135), we observed that 55% (32/58) were in X-linked genes, but 38% (22/58) were in autosomal genes, while the remaining 7% (4/58) had multiple variants in genes with different modes on inheritance. This study highlights that in families with multiple affected males, X linkage should not be assumed, and both individuals should be considered, as different genetic etiologies are common in apparent familial cases

Update of P2X receptor properties and their pharmacology: IUPHAR Review 30

The known seven mammalian receptor subunits (P2X1–7) form cationic channels gated by ATP. Three subunits compose a receptor channel. Each subunit is a polypeptide consisting of two transmembrane regions (TM1 and TM2), intracellular N- and C-termini, and a bulky extracellular loop. Crystallization allowed the identification of the 3D structure and gating cycle of P2X receptors. The agonist-binding pocket is located at the intersection of two neighbouring subunits. In addition to the mammalian P2X receptors, their primitive ligand-gated counterparts with little structural similarity have also been cloned. Selective agonists for P2X receptor subtypes are not available, but medicinal chemistry supplied a range of subtype-selective antagonists, as well as positive and negative allosteric modulators. Knockout mice and selective antagonists helped to identify pathological functions due to defective P2X receptors, such as male infertility (P2X1), hearing loss (P2X2), pain/cough (P2X3), neuropathic pain (P2X4), inflammatory bone loss (P2X5), and faulty immune reactions (P2X7)