Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

STIM1 and ORAI1 form a novel cold transduction mechanism in sensory and sympathetic neurons

ABSTRACT: Moderate coolness is sensed by TRPM8 ion channels in peripheral sensory nerves, but the mechanism by which extreme cold is detected remains elusive. Here we show that somatosensory and sympathetic neurons express two distinct mechanisms to detect noxious cold. In the first, cold-mediated/dependent inhibition of a background outward current causes membrane depolarization that activates an inward current through voltage‐dependent calcium (CaV) channels. A second cold‐activated mechanism is independent of membrane voltage, is inhibited by blockers of ORAI ion channels and by downregulation of STIM1, and is recapitulated in HEK293 cells by co‐expression of ORAI1 and STIM1. Using total internal reflection (TIRF) microscopy, we found that cold causes STIM1 to aggregate with and activate ORAI1 ion channels, in a mechanism similar to that underlying store‐operated calcium entry (SOCE), but directly activated by cold and not by emptying of calcium stores. This novel mechanism may explain the phenomenon of cold‐induced vasodilation (CIVD), in which extreme cold increases blood flow in order to preserve the integrity of peripheral tissues.

SUBMITTER: Dr. Tetsushi Kataura

PROVIDER: S-SCDT-10_15252-EMBJ_2022111372 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

STIM1 and ORAI1 form a novel cold transduction mechanism in sensory and sympathetic neurons.

Project description:Moderate coolness is sensed by TRPM8 ion channels in peripheral sensory nerves, but the mechanism by which noxious cold is detected remains elusive. Here, we show that somatosensory and sympathetic neurons express two distinct mechanisms to detect noxious cold. In the first, inhibition by cold of a background outward current causes membrane depolarization that activates an inward current through voltage-dependent calcium (CaV ) channels. A second cold-activated mechanism is independent of membrane voltage, is inhibited by blockers of ORAI ion channels and by downregulation of STIM1, and is recapitulated in HEK293 cells by co-expression of ORAI1 and STIM1. Using total internal reflection fluorescence microscopy we found that cold causes STIM1 to aggregate with and activate ORAI1 ion channels, in a mechanism similar to that underlying store-operated calcium entry (SOCE), but directly activated by cold and not by emptying of calcium stores. This novel mechanism may explain the phenomenon of cold-induced vasodilation (CIVD), in which extreme cold increases blood flow in order to preserve the integrity of peripheral tissues.

| S-EPMC9890232 | biostudies-literature

STIM1 and ORAI1 form a novel cold transduction mechanism in sensory and sympathetic neurons

Project description:Moderate coolness is sensed by TRPM8 ion channels in peripheral sensory nerves, but the mechanism by which extreme cold is detected remains elusive. Here we show that somatosensory and sympathetic neurons express two distinct mechanisms to detect noxious cold. In the first, cold-mediated/dependent inhibition of a background outward current causes membrane depolarization that activates an inward current through voltage‐dependent calcium (CaV) channels. A second cold‐activated mechanism is independent of membrane voltage, is inhibited by blockers of ORAI ion channels and by downregulation of STIM1, and is recapitulated in HEK293 cells by co‐expression of ORAI1 and STIM1. Using total internal reflection (TIRF) microscopy, we found that cold causes STIM1 to aggregate with and activate ORAI1 ion channels, in a mechanism similar to that underlying store‐operated calcium entry (SOCE), but directly activated by cold and not by emptying of calcium stores. This novel mechanism may explain the phenomenon of cold‐induced vasodilation (CIVD), in which extreme cold increases blood flow in order to preserve the integrity of peripheral tissues.

| S-SCDT-10_15252-EMBJ_2022111348 | biostudies-other

Activation of STIM1-Orai1 involves an intramolecular switching mechanism.

Project description:Stromal interaction molecule 1 (STIM1) stimulates calcium ion (Ca(2+)) entry through plasma membrane Orai1 channels in response to decreased Ca(2+) concentrations in the endoplasmic reticulum lumen. We identified an acidic motif within the STIM1 coiled-coil region that keeps its Ca(2+) activation domain [Ca(2+) release-activated Ca(2+) (CRAC) activation domain/STIM1-Orai activating region (CAD/SOAR)]-a cytoplasmic region required for its activation of Orai1-inactive. The sequence of the STIM1 acidic motif shows substantial similarity to that of the carboxyl-terminal coiled-coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region rendered STIM1 constitutively active, whereas mutations within a short basic segment of CAD/SOAR prevented Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing the basic segment to activate Orai1 channels. This evolutionarily conserved mechanism of STIM1 activation resembles the regulation of protein kinases by intramolecular silencing through pseudosubstrate binding.

| S-EPMC3408607 | biostudies-literature

Calmodulin dissociates the STIM1-Orai1 complex and STIM1 oligomers.

Project description:Store-operated calcium entry (SOCE) is a major pathway for calcium ions influx into cells and has a critical role in various cell functions. Here we demonstrate that calcium-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1. This interaction facilitates slow Ca2+-dependent inactivation after Orai1 channel activation by wild-type STIM1 or a constitutively active STIM1 mutant. We define the CaM-binding site in STIM1, which is adjacent to the STIM1-Orai1 coupling region. The binding of Ca2+-CaM to activated STIM1 disrupts the STIM1-Orai1 complex and also disassembles STIM1 oligomer. Based on these results we propose a model for the calcium-bound CaM-regulated deactivation of SOCE.

| S-EPMC5648805 | biostudies-literature

A pathogenic human Orai1 mutation unmasks STIM1-independent rapid inactivation of Orai1 channels.

Project description:Ca2+ release-activated Ca2+ (CRAC) channels are activated by direct physical interactions between Orai1, the channel protein, and STIM1, the endoplasmic reticulum Ca2+ sensor. A hallmark of CRAC channels is fast Ca2+-dependent inactivation (CDI) which provides negative feedback to limit Ca2+ entry through CRAC channels. Although STIM1 is thought to be essential for CDI, its molecular mechanism remains largely unknown. Here, we examined a poorly understood gain-of-function (GOF) human Orai1 disease mutation, L138F, that causes tubular aggregate myopathy. Through pairwise mutational analysis, we determine that large amino acid substitutions at either L138 or the neighboring T92 locus located on the pore helix evoke highly Ca2+-selective currents in the absence of STIM1. We find that the GOF phenotype of the L138 pathogenic mutation arises due to steric clash between L138 and T92. Surprisingly, strongly activating L138 and T92 mutations showed CDI in the absence of STIM1, contradicting prevailing views that STIM1 is required for CDI. CDI of constitutively open T92W and L138F mutants showed enhanced intracellular Ca2+ sensitivity, which was normalized by re-adding STIM1 to the cells. Truncation of the Orai1 C-terminus reduced T92W CDI, indicating a key role for the Orai1 C-terminus for CDI. Overall, these results identify the molecular basis of a disease phenotype with broad implications for activation and inactivation of Orai1 channels.

| S-EPMC9991058 | biostudies-literature

A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions.

Project description:STIM1 and Orai1 are the main components of a widely conserved Calcium influx pathway known as store-operated calcium entry (SOCE). STIM1 is a calcium sensor, which oligomerizes and activates Orai channels when calcium levels drop inside the endoplasmic reticulum (ER). The series of molecular rearrangements that STIM1 undergoes until final activation of Orai1 require the direct exposure of the STIM1 domain known as SOAR (Stim Orai Activating Region). In addition to these complex molecular rearrangements, other constituents like lipids at the plasma membrane, play critical roles orchestrating SOCE. PI(4,5)P2 and enriched cholesterol microdomains have been shown as important signaling platforms that recruit the SOCE machinery in steps previous to Orai1 activation. However, little is known about the molecular role of cholesterol once SOCE is activated. In this study we provide clear evidence that STIM1 has a cholesterol-binding domain located inside the SOAR region and modulates Orai1 channels. We demonstrate a functional association of STIM1 and SOAR to cholesterol, indicating a close proximity of SOAR to the inner layer of the plasma membrane. In contrast, the depletion of cholesterol induces the SOAR detachment from the plasma membrane and enhances its association to Orai1. These results are recapitulated with full length STIM1.

| S-EPMC4962086 | biostudies-literature

Bombyx mori homologs of STIM1 and Orai1 are essential components of the signal transduction cascade that regulates sex pheromone production.

Project description:Sex pheromone production in the pheromone gland (PG) of the silkmoth, Bombyx mori, is mediated by store-operated channels (SOCs) acting downstream of pheromone biosynthesis activating neuropeptide (PBAN) binding. Although recent studies have implicated STIM1 and Orai1 as essential components of SOCs, little is known about the molecular nature of the SOCs involved in sex pheromone production. In this study we cloned silkmoth homologs of STIM1 and Orai1 and sought to determine whether they comprise the PG SOC pathway. BmSTIM1 is expressed in multiple tissues and, in the PG, is encoded by two transcripts of differing size. BmOrai1A and BmOrai1B, which are identical except for a 37-residue N-terminal truncation in BmOrai1B, arise from alternative splicing of the bmorai1 locus and are expressed as independent transcripts in various tissues. In the PG, only BmOrai1B is actively transcribed. Fluorescent chimeras demonstrated that BmSTIM1 expression is restricted to the endoplasmic reticulum, whereas both BmOrai1A and BmOrai1B localize to the cell surface. In Ca(2+)-free medium, thapsigargin-mediated depletion of endoplasmic reticulum Ca(2+) stores resulted in redistribution of BmSTIM1 to the plasma membrane, but only when the BmOrai1 homologs were also overexpressed. Translocation was dependent on the BmSTIM1 C terminus "CRAC activation domain." Ala mutation of Lys(380), Lys(383), Lys(384), Arg(382), and Arg(385) suggests that translocation involves electrostatic interactions. Translocation was also seen following PBAN stimulation in cells co-expressing BmSTIM1, BmOrai1B, and the PBAN receptor. In vivo RNA interference-mediated knockdown of BmSTIM1 and BmOrai1 significantly reduced sex pheromone production without affecting cell viability.

| S-EPMC2781519 | biostudies-literature

IL-13 promotes sensory-sympathetic neurons crosstalk in asthma

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-03-23 | GSE228028 | GEO

STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization.

Project description:Tumor cells use broad spectrum proteolytic activity of plasmin to invade tissue and form metastatic foci. Cell surface-associated enolase-1 (ENO-1) enhances plasmin formation and thus participates in the regulation of pericellular proteolysis. Although increased levels of cell surface bound ENO-1 have been described in different types of cancer, the molecular mechanism responsible for ENO-1 exteriorization remains elusive. In the present study, increased ENO-1 protein levels were found in ductal breast carcinoma and on the cell surface of highly metastatic breast cancer cell line MDA-MB-231. Elevated cell surface-associated ENO-1 expression correlated with augmented MDA-MB-231 cell migratory and invasive properties. Exposure of MDA-MB-231 cells to LPS potentiated translocation of ENO-1 to the cell surface and its release into the extracellular space in the form of exosomes. These effects were independent of de novo protein synthesis and did not require the classical endoplasmic reticulum/Golgi pathway. LPS-triggered ENO-1 exteriorization was suppressed by pretreatment of MDA-MB-231 cells with the Ca(2+) chelator BAPTA or an inhibitor of endoplasmic reticulum Ca(2+)-ATPase pump, cyclopiazonic acid. In line with these observations, the stromal interaction molecule (STIM) 1 and the calcium release-activated calcium modulator (ORAI) 1-mediated store-operated Ca(2+) entry were found to regulate LPS-induced ENO-1 exteriorization. Pharmacological blockage or knockdown of STIM1 or ORAI1 reduced ENO-1-dependent migration of MDA-MB-231 cells. Collectively, our results demonstrate the pivotal role of store-operated Ca(2+) channel-mediated Ca(2+) influx in the regulation of ENO-1 exteriorization and thus in the modulation of cancer cell migratory and invasive properties.

| S-EPMC4424336 | biostudies-literature

STIM1 dimers undergo unimolecular coupling to activate Orai1 channels.

Project description:The endoplasmic reticulum (ER) Ca(2+) sensor, STIM1, becomes activated when ER-stored Ca(2+) is depleted and translocates into ER-plasma membrane junctions where it tethers and activates Orai1 Ca(2+) entry channels. The dimeric STIM1 protein contains a small STIM-Orai-activating region (SOAR)--the minimal sequence sufficient to activate Orai1 channels. Since SOAR itself is a dimer, we constructed SOAR concatemer-dimers and introduced mutations at F394, which is critical for Orai1 coupling and activation. The F394H mutation in both SOAR monomers completely blocks dimer function, but F394H introduced in only one of the dimeric SOAR monomers has no effect on Orai1 binding or activation. This reveals an unexpected unimolecular coupling between STIM1 and Orai1 and argues against recent evidence suggesting dimeric interaction between STIM1 and two adjacent Orai1 channel subunits. The model predicts that STIM1 dimers may be involved in crosslinking between Orai1 channels with implications for the kinetics and localization of Orai1 channel opening.

| S-EPMC4598629 | 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