Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Acid Sensing Ion Channel 2a Is Reduced in the Reduced Uterine Perfusion Pressure Mouse Model and Increases Seizure Susceptibility in Pregnant Mice.

ABSTRACT: Eclampsia is diagnosed in pregnant women who develop novel seizures. Our laboratory showed that the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia displays reduced latency to drug-induced seizures. While acid sensing ion channels (ASIC1a and 3) are important for reducing seizure longevity and severity, the role of ASIC2a in mediating seizure sensitivity in pregnancy has not been investigated. We hypothesized that 1) RUPP reduces hippocampal ASIC2a, and 2) pregnant mice with reduced ASIC2a (ASIC2a+/-) have increased seizure sensitivity. On gestational day 18.5, hippocampi from sham and RUPP C57BL/6 mice were harvested, and ASIC2a was assessed using Western blot. Pregnant wild-type and ASIC2a+/- mice received 40 mg/kg of pentylenetetrazol (i.p.) and were video recorded for 30 min. Behaviors were scored using a modified Racine scale (0-7: 0 = no seizure; 7 = respiratory arrest/death). Seizure severity was classified as mild (score = 1-3) or severe (score = 4-7). RUPP mice had reduced hippocampal and placental ASIC2a protein. ASIC2a+/- mice had reduced latency to seizures, increased seizure duration, increased severe seizure duration, and higher maximum seizure scores. Reduced hippocampal ASIC2a in RUPP mice and increased seizure activity in pregnant ASIC2a+/- mice support the hypothesis that reduced ASIC2a increases seizure sensitivity associated with the RUPP.

SUBMITTER: Jones-Muhammad M

PROVIDER: S-EPMC8151496 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Glucose Deficiency Elevates Acid-Sensing Ion Channel 2a Expression and Increases Seizure Susceptibility in Temporal Lobe Epilepsy.

Project description:Brain hypometabolism is a common epilepsy-related finding in both patients and animal models. Fluorodeoxyglucose positron emission tomography studies have shown that recurrent seizures lead to reduced glucose metabolism in certain brain regions, but no studies have definitively determined whether this induces epileptogenesis. There is evidence that acid-sensing ion channel 2a (ASIC2a) affects epilepsy susceptibility. Transcription factor CP2 (TFCP2) regulates ASIC2a expression. We report that suppressed TFCP2 expression and elevated ASIC2a expression were associated with glucose hypometabolism in the hippocampi of humans with epilepsy and of rat epilepsy model brains. In cultured PC12 cells, we determined that glucose deficiency led to TFCP2 downregulating ASIC2a. Moreover, electrophysiological recordings from cultured rat hippocampal slices showed that ASIC2a overexpression resulted in more action potentials in CA1 pyramidal neurons and increased seizure susceptibility. Our findings suggest that hippocampal glucose hypometabolism elevates ASIC2a expression by suppressing TFCP2 expression, which further enhances the intrinsic excitability of CA1 pyramidal neurons and increases seizure susceptibility in patients with temporal lobe epilepsy.

| S-EPMC5517604 | biostudies-literature

Amiloride-insensitive currents of the acid-sensing ion channel-2a (ASIC2a)/ASIC2b heteromeric sour-taste receptor channel.

Project description:Acid-sensing ion channel-2a (ASIC2a) is an amiloride-blockable proton-gated cation channel, probably contributing to sour-taste detection in rat taste cells. To isolate another subtype of the sour-taste receptor, we screened a rat circumvallate papilla cDNA library and identified ASIC2b, an N-terminal splice variant of ASIC2a. Reverse transcription-PCR analyses confirmed the expression of ASIC2b transcripts in the circumvallate papilla and, moreover, demonstrated its expression in the foliate and fungiform papillae. Immunohistochemical analyses revealed that ASIC2b, as well as ASIC2a, was expressed in a subpopulation of taste cells in the circumvallate, foliate, and fungiform papillae, and some of the cells displayed both ASIC2a and ASIC2b immunoreactivities. Subsequent coimmunoprecipitation studies with circumvallate papillae extracts indicated that ASIC2b associated with ASIC2a to form assemblies and, together with our immunohistochemical findings, strongly suggested that both ASIC2 subunits formed heteromeric channels in taste cells in the circumvallate, foliate, and fungiform papillae. Oocyte electrophysiology demonstrated that the ASIC2a/ASIC2b channel generated maximal inward currents at a pH of < or =2.0, which is in agreement with the in vivo pH sensitivity of rat taste cells, and that the amiloride sensitivity of the heteromer decreased with decreasing pH and was almost completely abolished at a pH of 2.0. These findings provide persuasive explanations for the amiloride insensitivity of acid-induced responses of rat taste cells.

| S-EPMC6742202 | biostudies-literature

Acid-Sensing Ion Channel 2a (ASIC2a) Promotes Surface Trafficking of ASIC2b via Heteromeric Assembly.

Project description:Acid-sensing ion channels (ASICs) are proton-activated cation channels that play important roles as typical proton sensors during pathophysiological conditions and normal synaptic activities. Among the ASIC subunits, ASIC2a and ASIC2b are alternative splicing products from the same gene, ACCN1. It has been shown that ASIC2 isoforms have differential subcellular distribution: ASIC2a targets the cell surface by itself, while ASIC2b resides in the ER. However, the underlying mechanism for this differential subcellular localization remained to be further elucidated. By constructing ASIC2 chimeras, we found that the first transmembrane (TM1) domain and the proximal post-TM1 domain (17 amino acids) of ASIC2a are critical for membrane targeting of the proteins. We also observed that replacement of corresponding residues in ASIC2b by those of ASIC2a conferred proton-sensitivity as well as surface expression to ASIC2b. We finally confirmed that ASIC2b is delivered to the cell surface from the ER by forming heteromers with ASIC2a, and that the N-terminal region of ASIC2a is additionally required for the ASIC2a-dependent membrane targeting of ASIC2b. Together, our study supports an important role of ASIC2a in membrane targeting of ASIC2b.

| S-EPMC4967927 | biostudies-literature

Acid-sensing ion channel (ASIC) 1a/2a heteromers have a flexible 2:1/1:2 stoichiometry.

Project description:Acid-sensing ion channels (ASICs) are widely expressed proton-gated Na(+) channels playing a role in tissue acidosis and pain. A trimeric composition of ASICs has been suggested by crystallization. Upon coexpression of ASIC1a and ASIC2a in Xenopus oocytes, we observed the formation of heteromers and their coexistence with homomers by electrophysiology, but could not determine whether heteromeric complexes have a fixed subunit stoichiometry or whether certain stoichiometries are preferred over others. We therefore imaged ASICs labeled with green and red fluorescent proteins on a single-molecule level, counted bleaching steps from GFP and colocalized them with red tandem tetrameric mCherry for many individual complexes. Combinatorial analysis suggests a model of random mixing of ASIC1a and ASIC2a subunits to yield both 2:1 and 1:2 ASIC1a:ASIC2a heteromers together with ASIC1a and ASIC2a homomers.

| S-EPMC4050600 | biostudies-literature

Reduced Uterine Perfusion Pressure (RUPP) Model of Preeclampsia in Mice.

Project description:Preeclampsia (PE) is a pregnancy-induced hypertension with proteinuria that typically develops after 20 weeks of gestation. A reduction in uterine blood flow causes placental ischemia and placental release of anti-angiogenic factors such as sFlt-1 followed by PE. Although the reduced uterine perfusion pressure (RUPP) model is widely used in rats, investigating the role of genes on PE using genetically engineered animals has been problematic because it has been difficult to make a useful RUPP model in mice. To establish a RUPP model of PE in mice, we bilaterally ligated ovarian vessels distal to ovarian branches, uterine vessels, or both in ICR-strain mice at 14.5 days post coitum (dpc). Consequently, these mice had elevated BP, increased urinary albumin excretion, severe endotheliosis, and mesangial expansion. They also had an increased incidence of miscarriage and premature delivery. Embryonic weight at 18.5 dpc was significantly lower than that in sham mice. The closer to the ligation site the embryos were, the higher the resorption rate and the lower the embryonic weight. The phenotype was more severe in the order of ligation at the ovarian vessels < uterine vessels < both. Unlike the RUPP models described in the literature, this model did not constrict the abdominal aorta, which allowed BP to be measured with a tail cuff. This novel RUPP model in mice should be useful for investigating the pathogenesis of PE in genetically engineered mice and for evaluating new therapies for PE.

| S-EPMC4871336 | biostudies-literature

Quercetin attenuates reduced uterine perfusion pressure -induced hypertension in pregnant rats through regulation of endothelin-1 and endothelin-1 type A receptor.

Project description:BackgroundQuercetin was reported to be crucial for a broad range of activities, including attenuating inflammation, platelet aggregation, capillary permeability, and lipid peroxidation. However, the effect of quercetin in hypertension during pregnancy, was not fully understood.MethodsThe model of hypertension in pregnancy was established in rats by reduced uterine perfusion pressure (RUPP). Quercetin was administrated by gavage. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured using the CODA 6 BP system. Plasma concentrations of Endothelin-1 (ET-1), soluble fms-like tyrosine kinase-1 (sFlt-1), and vascular endothelial growth factor (VEGF) were detected using enzyme-linked immunosorbent assay kits. The mRNA and protein levels of ET-1 and endothelin-1 type A receptor (ETAR) were determined by RT-PCR and Western blotting. The ETAR antagonist BQ-123 was performed by osmotic minipumps.ResultsIn RUPP induced rats, quercetin treatment decreased SBP and DBP, fetal resorptions percentage, plasma ET-1 and sFlt-1 concentrations, ET-1 and ETAR levels, but increased fetal body weight and VEGF expression. BQ-123 administration attenuated SBP and DBP, suppressed fatal resorptions percentage, and increased fetal body weight of RUPP rats.ConclusionQuercetin attenuates RUPP induced hypertension in pregnant rats through the regulation of ET-1 and ETAR.

| S-EPMC7409636 | biostudies-literature

Ion conduction and selectivity in acid-sensing ion channel 1.

Project description:The ability of acid-sensing ion channels (ASICs) to discriminate among cations was assessed based on changes in conductance and reversal potential with ion substitution. Human ASIC1a was expressed in Xenopus laevis oocytes, and acid-induced currents were measured using two-electrode voltage clamp. Replacement of extracellular Na(+) with Li(+), K(+), Rb(+), or Cs(+) altered inward conductance and shifted the reversal potentials consistent with a selectivity sequence of Li ∼ Na > K > Rb > Cs. Permeability decreased more rapidly than conductance as a function of atomic size, with P(K)/P(Na) = 0.1 and G(K)/G(Na) = 0.7 and P(Rb)/P(Na) = 0.03 and G(Rb)/G(Na) = 0.3. Stimulation of Cl(-) currents when Na(+) was replaced with Ca(2+), Sr(2+), or Ba(2+) indicated a finite permeability to divalent cations. Inward conductance increased with extracellular Na(+) in a hyperbolic manner, consistent with an apparent affinity (K(m)) for Na(+) conduction of 25 mM. Nitrogen-containing cations, including NH4(+), NH3OH(+), and guanidinium, were also permeant. In addition to passing through the channels, guanidinium blocked Na(+) currents, implying competition for a site within the pore. The role of negative charges in an external vestibule of the pore was evaluated using the point mutation D434N. The mutant channel had a decreased single-channel conductance, measured in excised outside-out patches, and a macroscopic slope conductance that increased with hyperpolarization. It had a weakened interaction with Na(+) (K(m) = 72 mM) and a selectivity that was shifted toward larger atomic sizes. We conclude that the selectivity of ASIC1 is based at least in part on interactions with binding sites both within and internal to the outer vestibule.

| S-EPMC4144671 | biostudies-literature

Abnormal cerebral microvascular perfusion and reactivity in female offspring of reduced uterine perfusion pressure (RUPP) mice model.

Project description:Children born from women with preeclampsia have alterations in cerebral neurovascular development and a high risk for developing cognitive alterations. Because cerebral blood vessels are critical components in cerebrovascular development, we evaluated the brain microvascular perfusion and microvascular reactivity (exposed to external stimuli of warm and cold) in pups born to preeclampsia-like syndrome based on the reduction of uterine perfusion (RUPP). Also, we evaluate the angiogenic proteomic profile in those brains. Pregnant mice showed a reduction in uterine flow after RUPP surgery (-40 to 50%) associated with unfavorable perinatal results compared to sham mice. Furthermore, offspring of the RUPP mice exhibited reduced brain microvascular perfusion at postnatal day 5 (P5) compared with offspring from sham mice. This reduction was preferentially observed in females. Also, brain microvascular reactivity to external stimuli (warm and cold) was reduced in pups of RUPP mice. Furthermore, a differential expression of the angiogenic profile associated with inflammation, extrinsic apoptotic, cancer, and cellular senescence processes as the primary signaling impaired process was found in the brains of RUPP-offspring. Then, offspring (P5) from preeclampsia-like syndrome exhibit impaired brain perfusion and microvascular reactivity, particularly in female mice, associated with differential expression of angiogenic proteins in the brain tissue.

| S-EPMC9670000 | biostudies-literature

Acid-sensing ion channel 3: An analgesic target.

Project description:Acid-sensing ion channel 3 (ASIC3) belongs to the epithelial sodium channel/degenerin (ENaC/DEG) superfamily. There are 7 different ASIC subunits encoded by 5 different genes. Most ASIC subunits form trimeric ion channels that upon activation by extracellular protons mediate a transient inward current inducing cellular excitability. ASIC subunits exhibit differential tissue expression and biophysical properties, and the ability of subunits to form homo- and heteromeric trimers further increases the complexity of currents measured and their pharmacological properties. ASIC3 is of particular interest, not only because it exhibits high expression in sensory neurones, but also because upon activation it does not fully inactivate: a transient current is followed by a sustained current that persists during a period of extracellular acidity, i.e. ASIC3 can encode prolonged acidosis as a nociceptive signal. Furthermore, certain mediators sensitize ASIC3 enabling smaller proton concentrations to activate it and other mediators can directly activate the channel at neutral pH. Moreover, there is a plethora of evidence using transgenic mouse models and pharmacology, which supports ASIC3 as being a potential target for development of analgesics. This review will focus on current understanding of ASIC3 function to provide an overview of how ASIC3 contributes to physiology and pathophysiology, examining the mechanisms by which it can be modulated, and highlighting gaps in current understanding and future research directions.

| S-EPMC7801124 | biostudies-literature

Amiloride docking to acid-sensing ion channel-1.

Project description:Amiloride is a small molecule diuretic, which has been used to dissect sodium transport pathways in many different systems. This drug is known to interact with the epithelial sodium channel and acid-sensing ion channel proteins, as well as sodium/hydrogen antiporters and sodium/calcium exchangers. The exact structural basis for these interactions has not been elucidated as crystal structures of these proteins have been challenging to obtain, though some involved residues and domains have been mapped. This work examines the interaction of amiloride with acid-sensing ion channel-1, a protein whose structure is available using computational and experimental techniques. Using molecular docking software, amiloride and related molecules were docked to model structures of homomeric human ASIC-1 to generate potential interaction sites and predict which analogs would be more or less potent than amiloride. The predictions made were experimentally tested using whole-cell patch clamp. Drugs previously classified as NCX or NHE inhibitors are shown to also inhibit hASIC-1. Potential docking sites were re-examined against experimental data to remove spurious interaction sites. The voltage sensitivity of inhibitors was also examined. Using the aggregated data from these computational and experimental experiments, putative interaction sites for amiloride and hASIC-1 have been defined. Future work will experimentally verify these interaction sites, but at present this should allow for virtual screening of drug libraries at these putative interaction sites.

| S-EPMC2843212 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data