Modulation Of Entry Research Articles

The Interaction of Calcium Entry and Calcium Sensitization in the Control of Vascular Tone and Blood Pressure of Normotensive and Hypertensive Rats

Increased systemic vascular resistance is responsible for blood pressure (BP) elevation in most forms of human or experimental hypertension. The enhanced contractility of structurally remodeled resistance arterioles is mediated by enhanced calcium entry (through L type voltage-dependent calcium channels - L-VDCC) and/or augmented calcium sensitization (mediated by RhoA/Rho kinase pathway). It is rather difficult to evaluate separately the role of these two pathways in BP control because BP response to the blockade of either pathway is always dependent on the concomitant activity of the complementary pathway. Moreover, vasoconstrictor systems enhance the activity of both pathways, while vasodilators attenuate them. The basal fasudil-sensitive calcium sensitization determined in rats deprived of endogenous renin-angiotensin system (RAS) and sympathetic nervous system (SNS) in which calcium entry was dose-dependently increased by L-VDCC opener BAY K8644, is smaller in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto (WKY) rats. In contrast, if endogenous RAS and SNS were present in intact rats, fasudil caused a greater BP fall in SHR than WKY rats. Our in vivo experiments indicated that the endogenous pressor systems (RAS and SNS) augment calcium sensitization mediated by RhoA/Rho kinase pathway, whereas the endogenous vasodilator systems (such as nitric oxide) attenuate this pathway. However, the modulation of calcium entry and calcium sensitization by nitric oxide is strain-dependent because NO deficiency significantly augments low calcium entry in WKY and low calcium sensitization in SHR. Further in vivo and in vitro experiments should clarify the interrelationships between endogenous vasoactive systems and the contribution of calcium entry and/or calcium sensitization to BP maintenance in various forms of experimental hypertension.

Design for Entry Module of Intelligent-entry EMR System

AbstractIn this article, an Electronic Medical Record (EMR) entry module is proposed originally through analyzing the language features of medical records. The medical staff can complete the majority of entry work by clicking options, through deconstructing the medical record language into phrases and presenting these phrases in the form of options, and the medical staff can write the medical records on tablet Personal Computers (PCs) beside the beds, thereby greatly improving the efficiency, timeliness and accuracy of the documentation of medical records.

Modulation of oxidative stress, apoptosis, and calcium entry in leukocytes of patients with multiple sclerosis by Hypericum perforatum

ObjectivesHypericum perfortarum (HP, St John's wort) is a modulator of Ca2+ entry in neutrophils and it may modulate intracellular free Ca2+ ([Ca2+]i) entry in leukocytes of patients with multiple sclerosis (MS). We investigated effects of HP on oxidative stress, apoptosis, and [Ca2+]i concentrations in serum and leukocytes of patients with MS.MethodsNeutrophils of nine newly diagnosed MS patients and nine healthy subjects within four subgroups were used in the study. The first group was a control; the second group was patients with MS. The neutrophils from patient group were incubated non-specific TRPM2 channel blocker (2-APB), voltage-gated calcium channel blockers, verapamil and diltiazem (V + D) with HP before N-formyl-L-methionyl-L-leucyl-L-phenylalanine stimulation, respectively.ResultsNeutrophil and serum lipid peroxidation, neutrophil apoptosis and [Ca2+]i levels in patients with MS were higher than in control although their levels were decreased by HP, 2-APB, and V + D incubations. The modulator role of V + D in MS and MS + HP groups was higher than in the 2-APB group. Neutrophilic glutathione peroxidase (GSH-Px) and serum vitamin A and E concentrations were lower in the MS group than in control. However, the neutrophil GSH-Px activity was increased by HP incubation. The neutrophil reduced glutathione, serum vitamin C and β-carotene concentrations did not change in control and patients.DiscussionWe observed that HP-induced protective effects on oxidative stress and [Ca2+]i concentrations by modulating transient receptor potential and voltage gated calcium channel in the patients with MS. Thus, it may provide useful treatment of neutrophil activity in the patients.

Do screencasts help to revise prerequisite mathematics? An investigation of student performance and perception

Basic calculus skills that are prerequisites for advanced mathematical studies continue to be a problem for a significant proportion of higher education students. While there are many types of revision material that could be offered to students, in this paper we investigate whether short, narrated video recordings of mathematical explanations (screencasts) are a useful tool to enhance student learning when revisiting prerequisite topics. We report on the outcomes of a study that was designed to both measure change in student performance before and after watching screencasts, and to capture students’ perception of the usefulness of screencasts in their learning. Volunteers were recruited from students enrolled on an entry module for the Mathematics Master of Science programme at the Open University to watch two screencasts sandwiched between two online calculus quizzes. A statistical analysis of student responses to the quizzes shows that screencasts can have a positive effect on student performance. Further analysis of student feedback shows that student confidence was increased by watching the screencasts. Student views on the value of screencasts for their learning indicated that they appreciated being able towatch a problem being solved and explained by an experienced mathematician;hear the motivation for a particular problem-solving approach;engage more readily with the material being presented, thereby retaining it more easily.The positive student views and impact on student scores indicate that short screencasts could play a useful role in revising prerequisite mathematics.

The V1/V2 loop of HIV-1 gp120 is necessary for Tat binding and consequent modulation of virus entry

Preventing cell entry of human immunodeficiency virus 1 (HIV-1) is of interest for the development of innovative therapies. We previously reported a specific interaction between HIV-1 envelope glycoprotein 120 (gp120) and Tat at the cell surface, which enhances virus attachment and entry. We also identified a gp120-mimicking peptide, CT319, that competes with gp120 for Tat binding, thus inhibiting HIV-1 infection. Here we report a molecular dissection of gp120 regions involved in this mechanism. Our findings identify the V1/V2 loop of gp120 as involved in Tat binding, and define this interaction as functionally relevant for HIV-1 entry into host cells.

STIM2 drives calcium oscillations through store-operated calcium entry caused by mild store depletion (P1160)

Abstract The main source of calcium in T cells is through a mechanism known as store-operated calcium entry (SOCE). STIM1 and STIM2 serve as ER calcium sensors that, upon store depletion, activate calcium release-activated calcium (CRAC) channels (Orai1-3,CRACM1-3) in the plasma membrane. In the absence of sustained calcium influx through CRAC channels, numerous lymphocyte functions are severely compromised, as demonstrated in patients suffering from SCID. Agonist-induced calcium oscillations in many cell types are triggered by calcium release from intracellular stores and driven by SOCE. However, their relative roles in agonist-mediated calcium oscillations remain ambiguous. We here report that while both STIM1 and STIM2 contribute to store-refilling during calcium oscillations in T cells, RBL and HEK cells, they do so dependent on the level of store depletion. Molecular silencing of STIM2 by siRNA or inhibition by G418 selectively suppresses SOCE and agonist-mediated calcium oscillations at low levels of store depletion, without interfering with STIM1-mediated signals induced by full store depletion. Thus, STIM2 is preferentially activated by low-level physiological agonist concentrations that cause mild reductions in ER calcium levels. We conclude that with increasing agonist concentrations, SOCE is mediated initially by endogenous STIM2 and incrementally by STIM1, enabling differential modulation of calcium entry over a range of stimulus intensities and levels of store depletion.

The polybasic lysine-rich domain of plasma membrane-resident STIM1 is essential for the modulation of store-operated divalent cation entry by extracellular calcium

STIM1 acts as an endoplasmic reticulum Ca2+ sensor that communicates the filling state of the intracellular stores to the store-operated channels. In addition, STIM1 is expressed in the plasma membrane, with the Ca2+ binding EF-hand motif facing the extracellular medium; however, its role sensing extracellular Ca2+ concentrations in store-operated Ca2+ entry (SOCE), as well as the underlying mechanism remains unclear. Here we report that divalent cation entry stimulated by thapsigargin (TG) is attenuated by extracellular Ca2+ in a concentration-dependent manner. Expression of the Ca2+-binding defective STIM1(D76A) mutant did not alter the surface expression of STIM1 but abolishes the regulation of divalent cation entry by extracellular Ca2+. Orai1 and TRPC1 have been shown to play a major role in SOCE. Expression of the STIM1(D76A) mutant did not alter Orai1 phosphoserine content. TRPC1 silencing significantly attenuated TG-induced Mn2+ entry. Expression of the STIM1(K684,685E) mutant impaired the association of plasma membrane STIM1 with TRPC1, as well as the regulation of TG-induced divalent cation entry by extracellular Ca2+, which suggests that TRPC1 might be involved in the regulation of divalent cation entry by extracellular Ca2+ mediated by plasma membrane-resident STIM1. Expression of the STIM1(D76A) or STIM1(K684,685E) mutants reduced store-operated divalent cation entry and resulted in loss of dependence on the extracellular Ca2+ concentration, providing evidence for a functional role of plasma membrane-resident STIM1 in the regulation of store-operated divalent cation entry, which at least involves the EF-hand motif and the C-terminal polybasic lysine-rich domain.

Hepatitis C Virus Envelope Glycoprotein Signatures Are Associated With Treatment Failure and Modulation of Viral Entry and Neutralization

A major challenge for antiviral treatment of hepatitis C virus (HCV) infection is viral resistance, potentially resulting from the high variability of HCV envelope glycoproteins and subsequent selection of strains with enhanced infectivity and/or immune escape. We used a bioinformatics and functional approach to investigate whether E1/E2 envelope glycoprotein structure and function were associated with treatment failure in 92 patients infected with HCV genotype 1. Bioinformatics analysis identified 1 sustain virological response (R)-related residue in E1 (219T) and 2 non-SVR (NR)-related molecular signatures in E2 (431A and 642V) in HCV genotype 1a. Two of these positions also appeared in minimal networks separating NR patients from R patients. HCV pseudoparticles (HCVpp) expressing 431A and 642V resulted in a decrease in antibody-mediated neutralization by pretreatment sera. 431A/HCVpp entry into Huh7.5 cells increased with overexpression of CD81 and SR-BI. Moreover, an association of envelope glycoprotein signatures with treatment failure was confirmed in an independent cohort (Virahep-C). Combined in silico and functional analyses demonstrate that envelope glycoprotein signatures associated with treatment failure result in an alteration of host cell entry factor use and escape from neutralizing antibodies, suggesting that virus-host interactions during viral entry contribute to treatment failure.

Amyloid precursor protein-mediated modulation of capacitive calcium entry

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. In the present study, the function of amyloid precursor protein (APP) in modulating capacitive calcium entry (CCE), a refilling mechanism for depleted intracellular calcium stores, was investigated. CCE in neural 2a (N2a) cells stably expressing wild-type human APP was lower than in wild-type N2a cells, while CCE in APP knockout mouse embryonic fibroblast (MEF) cells was higher than in their wild-type counterparts. We demonstrate that wild-type APP depresses CCE. Furthermore, using N2a cells transfected with C-terminal APP fragments, we show that these fragments anchored in the cell membrane play an important role in CCE depression.

Mitochondrial modulation of store-operated Ca2+ entry in model cells of Alzheimer’s disease

Mitochondrial malfunction and calcium dyshomeostasis are early pathological events considered as important features of the Alzheimer’s disease (AD) brain. Recent studies have suggested mitochondrion as an active regulator of Ca2+ signaling based on its calcium buffering capacity. Herein, we investigated the mitochondrial involvement in the modulation of store-operated calcium entry (SOCE) in neural 2a (N2a) transgenic AD model cells. Results showed that SOCE was significantly depressed in N2a cells transfected with wild-type human APP695 (N2a APPwt) compared with empty vector control (N2a WT) cells. Pharmacological manipulation with mitochondrial function blockers, such as FCCP, RuR, or antimycin A/oligomycin, could inhibit mitochondrial calcium handling, and then impair SOCE pathway in N2a WT cells. Furthermore, mitochondria of N2a APPwt cells exhibited more severe swelling in response to Ca2+, which is an indication of mitochondrial membrane permeability transition (MPT), than the wild-type controls. Additionally, treatment with cyclosporin A, a potent inhibitor of cyclophilin D, which can block MPT, could significantly restore the attenuated SOCE in N2a APPwt cells. Therefore, inhibition of cyclophilin D might be a therapeutic strategy for Alzheimer’s disease.

HIAD – hydrogen incident and accident database

The Hydrogen Incident and Accident Database (HIAD) is being developed as a repository of systematic data describing in detail hydrogen-related undesired events (incidents or accidents). It is an open web-based information system serving various purposes such as a data source for lessons learnt, risk communication and partly risk assessment. The paper describes the features of the three HIAD modules – the Data Entry Module (DEM), the Data Retrieval Module (DRM) and the Data Analysis Module (DAM) – and the potential impact the database may have on hydrogen safety. The importance of data quality assurance process is also addressed.

1α,25-Dihydroxyvitamin D3 mechanism of action: Modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats

The involvement of calcium-mediated signaling pathways in the mechanism of action of 1α,25-dihydroxyvitamin D3 (1,25D) is currently demonstrated. In this study we found that 1,25D induces nongenomic effects mediated by membrane vitamin D receptor (VDRm) by modulating intermediate filament (IF) phosphorylation and calcium uptake through L-type voltage-dependent calcium channels (L-VDCC) in cerebral cortex of 10day-old rats. Results showed that the mechanism of action of 1,25D involves intra- and extracellular calcium levels, as well as the modulation of chloride and potassium channels. The effects of L-VDCCs on membrane voltage occur over a broad potential range and could involve depolarizing or hyperpolarizing coupling modes, supporting a cross-talk among Ca2+ uptake and potassium and chloride channels. Also, the Na+/K+-ATPase inactivation by ouabain mimicked the 1,25D action on 45Ca2+ uptake. The Na+/K+-ATPase inhibition observed herein might lead to intracellular Na+ accumulation with subsequent L-VDCC opening and consequently increased 45Ca2+ (calcium, isotope of mass 45) uptake. Moreover, the 1,25D effect is dependent on the activation of the following protein kinases: cAMP‐dependent protein kinase (PKA), Ca2+/calmodulin‐dependent protein kinase (PKCaMII), phosphatidylinositol 3‐kinase (PI3K) and mitogen‐activated protein kinase p38 (p38MAPK). The modulation of calcium entry into neural cells by the 1,25D we are highlighting, might take a role in the regulation of a plethora of intracellular processes. Considering that vitamin D deficiency can lead to brain illness, 1,25D may be a possible candidate to be used, at least as an adjuvant, in the pharmacological therapy of neuropathological conditions.

Sigma-1 receptors do not regulate calcium influx through voltage-dependent calcium channels in mouse brain synaptosomes

Several lines of evidence suggest that σ1 receptors regulate intracellular calcium concentration [Ca2+]i. However, no previous studies have demonstrated a consistent role for these receptors in the modulation of extracellular calcium entry through plasmalemmal voltage-dependent calcium channels (VDCCs). To search for evidence of such a role we compared [Ca2+]i under basal conditions and after depolarization with KCl in fura-2-loaded synaptosomes from wild-type and σ1 receptor knockout (σ1R-KO) mice. We also tested the effects of the selective σ1 receptor agonists PRE-084 and (+)-pentazocine and antagonists BD-1047 and NE-100 on the increase in [Ca2+]i induced by depolarization with 60mM KCl. Mibefradil, a nonselective blocker of VDCCs, was used as a positive control. Basal [Ca2+]i and the increase in [Ca2+]i caused by KCl-induced depolarization were similar in brain synaptosomes from both wild-type and σ1R-KO mice. Mibefradil (1–30μM) and all σ1 receptor ligands studied (3–100μM) inhibited the KCl-induced increase in [Ca2+]i in a concentration-dependent way. The order of maximum inhibition for the ligands compared here was NE-100>BD-1047=PRE 084>(+)-pentazocine. There were no appreciable differences in their effects between wild-type and σ1R-KO mice. These findings indicate that σ1 receptors are not involved in calcium influx through VDCCs or in the inhibitory effects of these σ1 ligands on Ca2+ channels.

Increasing Adoption of Computerized Provider Order Entry, and Persistent Regional Disparities, in US Emergency Departments

The US government provides financial incentives for "meaningful use" of health information technology, including computerized provider order entry. We assess prevalence of emergency department (ED) computerized provider order entry in 4 states, identify characteristics predicting computerized provider order entry adoption, and assess adoption in 1 state over time, all before incentive programs. We surveyed all nonfederal EDs in Massachusetts, Colorado, Georgia, and Oregon, assessing health information technology prevalence in 2008, focusing on computerized provider order entry, an enabler of other health information technology and a key element in itself. We use multivariable logistic regression to evaluate predictors of adoption. We compared the Massachusetts data with data from a similar survey we conducted for Massachusetts in 2005, using 95% confidence intervals (CIs) to assess the change in rate. We identified and surveyed 351 EDs, and 290 (83%) responded to the computerized provider order entry module. Of these, 30% had adopted computerized provider order entry. Odds of computerized provider order entry in rural EDs were 0.07 relative to urban (95% CI 0.01 to 0.39). Oregon EDs had a higher likelihood of computerized provider order entry adoption than Georgia EDs, the state with the lowest adoption (odds ratio 2.9; 95% CI 1.2 to 7.3). In 2005, 15% of Massachusetts EDs reported computerized provider order entry versus 44% in 2008 (29% difference; 95% CI 26% to 32%). Health information technology adoption varies by state and urbanicity, with less computerized provider order entry in rural EDs. ED computerized provider order entry adoption nearly tripled in Massachusetts from 2005 to 2008, before any financial inducements. Federal resources might be more effective if they helped providers select health information technology tools, improve health information technology design, and evaluate its influence on care delivery, versus simply calling for "more".

Rational design of artificial riboswitches based on ligand-dependent modulation of internal ribosome entry in wheat germ extract and their applications as label-free biosensors

Riboswitches are RNA elements in mRNA that control gene expression in cis in response to their specific ligands. Because artificial riboswitches make it possible to regulate any gene with an arbitrary molecule, they are expected to function as biosensors, in which the output is easily detectable protein expression. I report herein a fully rational design strategy for artificially constructing novel riboswitches that work in a eukaryotic cell-free translation system (wheat germ extract). In these riboswitches, translation mediated by an internal ribosome entry site (IRES) is promoted only in the presence of a specific ligand (ON), while it is inhibited in the absence of the ligand (OFF). The first rationally designed riboswitch, which is regulated by theophylline, showed a high switching efficiency and dependency on theophylline. In addition, based on the design of the theophylline-dependent riboswitch, other three kinds of riboswitches controlled by FMN, tetracycline, and sulforhodamine B, were constructed only by calculating the ΔG value of one stem-loop structure. The rational design strategy described herein is therefore useful for easily producing various ligand-dependent riboswitches, which are available as biosensors for detecting their ligands.

Kainate‐induced toxicity in the hippocampus: potential role of lithium

We investigated the neuroprotective effects of lithium in an experimental neurodegeneration model gated to kainate (KA) receptor activation. The hippocampus from KA-treated mice and hippocampal cell cultures were used to evaluate the pathways regulated by chronic lithium pretreatment in both in vivo and in vitro models. Treatment with KA, as measured by fragmentation of alpha-spectrin and biochemically, induced the activation of calpain resulting in p35 cleavage to p25, indicating activation of cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3ss (GSK-3ss) and an increase in tau protein phosphorylation. Treatment with lithium reduced calpain activation and reduced the effects of cdk5 and GSK-3ss on tau. KA treatment of cultures resulted in neuronal demise. According to nuclear condensed cell counts, the addition of lithium to neuronal cell cultures (0.5-1 mM) a few days before KA treatment had neuroprotective and also antiapoptotic effects. The action of lithium on calpain/cdk5 and GSK-3ss pathways produced similar results in vivo. As calpain is activated by an increase in intracellular calcium, we showed that lithium reduced calcium concentrations in basal and KA-treated hippocampal cells, which was accompanied by an increase in NCX3, a Na+/Ca2+ exchanger pump. A robust neuroprotective effect of lithium in the excitotoxic process induced by KA in mouse hippocampus was demonstrated via modulation of calcium entry and the subsequent inhibition of the calpain pathway. These mechanisms may act in an additive way with other mechanisms previously described for lithium, suggesting that it may be useful as a possible therapeutic strategy for Alzheimer's disease.

Multicenter data acquisition made easy

BackgroundThe process for data collection in multicenter trials may be troublesome and expensive. We report our experience with the spreadsheet function in Googledocs for this purpose.MethodsIn Googledocs the data manager creates a form similar to the paper case record form, which will function as a decentral data entry module. When the forms are submitted, they are presented in a spreadsheet in Googledocs, which can be exported to different standard spreadsheet formats.ResultsFor a multicenter randomized clinical trial with five different participating hospitals we created a decentral data entry module using the spreadsheet function in Googledocs. The study comprised 332 patients (clinicaltrials.gov identifier: NCT00815698) with five visits per patient. One person at each study site entered data from the original paper based case report forms which were kept at the study sites as originals. We did not experience any technical problems using the system.ConclusionsThe system allowed for decentral data entry, and it was easy to use, safe, and free of charge. The spreadsheet function in Googledocs may potentially replace current expensive solutions for data acquisition in multicenter trials.Trial registrationclinicaltrials.gov NCT00815698

Growth-dependent modulation of capacitative calcium entry in normal rat kidney fibroblasts

Normal rat kidney (NRK) fibroblasts have electrophysiological properties and intracellular calcium dynamics that are dependent upon their growth stage. In the present study we show that this differential behavior coincides with a differential calcium entry that can be either capacitative or non-capacitative. Confluent cells made quiescent by serum deprivation, which have a stable membrane potential near − 70 mV and do not show spontaneous intracellular calcium oscillations, primarily exhibit the capacitative mechanism for calcium entry, also called store-operated calcium entry (SOCE). When the quiescent cells are grown to density-arrest in the presence of EGF as the sole polypeptide growth factor, these cells characteristically fire spontaneously repetitive calcium action potentials, which propagate throughout the whole monolayer and are accompanied by intracellular calcium transients. These density-arrested cells appear to exhibit in addition to SOCE also receptor-operated calcium entry (ROCE) as a mechanism for calcium entry. Furthermore we show that, in contrast to earlier studies, the employed SOCs and ROCs are permeable for both calcium and strontium ions. We examined the expression of the canonical transient receptor potential channels (Trpcs) that may be involved in SOCE and ROCE. We show that NRK fibroblasts express the genes encoding Trpc1, Trpc5 and Trpc6, and that the levels of their expression are dependent upon the growth stage of the cells. In addition we examined the growth stage dependent expression of the genes encoding Orai1 and Stim1, two proteins that have recently been shown to be involved in SOCE. Our results suggest that the differential expression of Trpc5, Trpc6, Orai1 and Stim1 in quiescent and density-arrested NRK fibroblasts is responsible for the difference in regulation of calcium entry between these cells. Finally, we show that inhibition or potentiation of SOCE and ROCE by pharmacological agents has profound effects on calcium dynamics in NRK fibroblasts.

Different role of cAMP dependent protein kinase and CaMKII in H3 receptor regulation of histamine synthesis and release

Histamine H3 autoreceptors induce a negative feedback on histamine synthesis and release. While it is known that cAMP/cAMP dependent protein kinase (PKA) and Ca2+/CaMKII transduction pathways mediate H3 effects on histamine synthesis, the pathways regulating neuronal histamine release are poorly known. Given the potential use of H3 ligands in cognitive diseases, we have developed a technique for the determination of H3 effects on histamine synthesis and release in brain cortical miniprisms. Potassium-induced depolarization effects were impaired by blockade of calcium entry through N and P/Q channels, as well as of CaMKII, but release was not affected by activators or inhibitors of the cAMP/PKA pathway (1-methyl-3-isobutylxanthine (IBMX), N6,2′-O-dibutyryladenosine 3′,5′-cyclic monophosphate sodium salt (db–cAMP) or myristoyl PKA inhibitor peptide 14-22 (PKI14-22). In contrast, forskolin stimulated histamine release, although independently of PKA. Stimulation of histamine H3 receptors with the agonist imetit markedly reduced the depolarization increase of histamine release, apparently through P/Q calcium channel inhibition. The H3 antagonist/inverse agonist thioperamide modestly stimulated histamine release. Thioperamide effect on release was not modified by the PKA inhibitor PKI14-22, but it was blocked by the CaMKII inhibitor KN-62. These results indicate that H3 autoreceptors regulate neuronal histamine release (1) independently of the cAMP/PKA cascade, and (2) through modulation of calcium entry and CaMKII activation during depolarization.

Structurally delineating stromal interaction molecules as the endoplasmic reticulum calcium sensors and regulators of calcium release‐activated calcium entry

The endoplasmic reticulum (ER) lumen stores a crucial source of calcium (Ca2+) maintained orders of magnitude higher than the cytosol for the activation of a plethora of cellular responses transmitted in health and disease by a mutually efficient and communicative exchange of Ca2+ between compartments. A coordination of the Ca2+ signal is evident in the development of Ca2+ release-activated Ca2+ (CRAC) entry, vital to lymphocyte activation and replenishing of the ER Ca2+ stores, where modest decreases in ER luminal Ca2+ induce sustained increases in cytosolic Ca2+ sourced from steadfast extracellular Ca2+ supplies. While protein sensors that transduce Ca2+ signals in the cytosol such as calmodulin are succinctly understood, comparative data on the ER luminal Ca2+ sensors is only recently coming to light with the discovery that stromal interaction molecules (STIMs) sense variations in ER stored Ca2+ levels in the functional regulation of plasma membrane Orai proteins, the major component of CRAC channel pores. Drawing from data on the role of STIMs in the modulation of CRAC entry, this review illustrates the structural features that delimit the functional characteristics of ER Ca2+ sensors relative to well known cytoplasmic Ca2+ sensors.