In electrically nonexcitable cells, Ca2+ influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and prolifera...

Store-operated calcium channels.

The microvascular endothelial cell monolayer localized at the critical interface between the blood and vessel wall has the vital functions of regulating tissue fluid balance and supplying the essential nutrients needed for the survival of the organism. The endothelial cell is an exquisite "sensor" that responds to diverse signals generated in the blood, subendothelium, and interacting cells. The endothelial cell is able to dynamically regulate its paracellular and transcellular pathways for transport of plasma proteins, solutes, and liquid. The semipermeable characteristic of the endothelium (which distinguishes it from the epithelium) is crucial for establishing the transendothelial protein gradient (the colloid osmotic gradient) required for tissue fluid homeostasis. Interendothelial junctions comprise a complex array of proteins in series with the extracellular matrix constituents and serve to limit the transport of albumin and other plasma proteins by the paracellular pathway. This pathway is highly regulated by the activation of specific extrinsic and intrinsic signaling pathways. Recent evidence has also highlighted the importance of the heretofore enigmatic transcellular pathway in mediating albumin transport via transcytosis. Caveolae, the vesicular carriers filled with receptor-bound and unbound free solutes, have been shown to shuttle between the vascular and extravascular spaces depositing their contents outside the cell. This review summarizes and analyzes the recent data from genetic, physiological, cellular, and morphological studies that have addressed the signaling mechanisms involved in the regulation of both the paracellular and transcellular transport pathways.

https://www.physiology.org/doi/pdf/10.1152/physrev.00012.2005

Signaling Mechanisms Regulating Endothelial Permeability

This review covers current knowledge of selenium in the environment, dietary intakes, metabolism and status, functions in the body, thyroid hormone metabolism, antioxidant defense systems and oxidative metabolism, and the immune system. Selenium toxicity and links between deficiency and Keshan disease and Kashin-Beck disease are described. The relationships between selenium intake/status and various health outcomes, in particular gastrointestinal and prostate cancer, cardiovascular disease, diabetes, and male fertility, are reviewed, and recent developments in genetics of selenoproteins are outlined. The rationale behind current dietary reference intakes of selenium is explained, and examples of differences between countries and/or expert bodies are given. Throughout the review, gaps in knowledge and research requirements are identified. More research is needed to improve our understanding of selenium metabolism and requirements for optimal health. Functions of the majority of the selenoproteins await characterization, the mechanism of absorption has yet to be identified, measures of status need to be developed, and effects of genotype on metabolism require further investigation. The relationships between selenium intake/status and health, or risk of disease, are complex but require elucidation to inform clinical practice, to refine dietary recommendations, and to develop effective public health policies.

Selenium in human health and disease.

TRP channels: an overview.

Pole development is coordinated with the Caulobacter crescentus cell cycle by two-component signaling proteins. We show that an unusual response regulator, PleD, is required for polar differentiation and is sequestered to the cell pole only when it is activated by phosphorylation. Dynamic localization of PleD to the cell pole provides a mechanism to temporally and spatially control the signaling output of PleD during development. Targeting of PleD to the cell pole is coupled to the activation of a C-terminal guanylate cyclase domain, which catalyzes the synthesis of cyclic di-guanosine monophosphate. We propose that the local action of this novel-type guanylate cyclase might constitute a general regulatory principle in bacterial growth and development.

/pdf/cell-cycle-dependent-dynamic-localization-of-a-bacterial-35ndfubt01.pdf

Cell cycle-dependent dynamic localization of a bacterial response regulator with a novel di-guanylate cyclase output domain

SPECIFIC AIMTo determine whether host selenium (Se) deficiency can induce changes in the genome of a replicating influenza virus such that a normally mild virus converts into a more virulent strain and to characterize such genomic changes.PRINCIPAL FINDINGS1. Replication of a mild strain of influenza virus in Se-deficient mice results in a novel virulent strain that causes severe lung pathology even when passed into Se-adequate miceSe-deficient mice developed much more severe lung pathology postinfection with influenza virus than Se-adequate infected mice. To determine whether host factors or viral factors were responsible for the increased pathogenicity of influenza virus that had replicated in Se-deficient mice, a passage experiment was performed. We infected groups of Se-adequate and Se-deficient mice with influenza A/Bangkok/1/79 (H3N2). At 5 days postinfection, the mice were killed and virus was recovered from the lungs. Five separate isolates from each group of mice were used to inoculate five indiv...

/pdf/host-nutritional-selenium-status-as-a-driving-force-for-4slett99k1.pdf

Host nutritional selenium status as a driving force for influenza virus mutations.

Acute transitions in cytosolic calcium ([Ca2+]i) through store-operated calcium entry channels catalyze interendothelial cell gap formation that increases permeability. However, the rise in [Ca2+]i only disrupts barrier function in the absence of a rise in cAMP. Discovery that type 6 adenylyl cyclase (AC6; EC 4.6.6.1) is inhibited by calcium entry through store-operated calcium entry pathways provided a plausible explanation for how inflammatory [Ca2+]i mediators may decrease cAMP necessary for endothelial cell gap formation. [Ca2+]i mediators only modestly decrease global cAMP concentrations and thus, to date, the physiological role of AC6 is unresolved. Present studies used an adenoviral construct that expresses the calcium-stimulated AC8 to convert normal calcium inhibition into stimulation of cAMP, within physiologically relevant concentration ranges. Thrombin stimulated a dose-dependent [Ca2+]i rise in both pulmonary artery (PAECs) and microvascular (PMVEC) endothelial cells, and promoted intercellular gap formation in both cell types. In PAECs, gap formation was progressive over 2 h, whereas in PMVECs, gap formation was rapid (within 10 min) and gaps resealed within 2 h. Expression of AC8 resulted in a modest calcium stimulation of cAMP, which virtually abolished thrombin-induced gap formation in PMVECs. Findings provide the first direct evidence that calcium inhibition of AC6 is essential for endothelial gap formation.

https://rupress.org/jcb/article-pdf/157/7/1267/1305078/jcb15771267.pdf

Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase.

Store-operated calcium (SOC) entry represents the principal Ca 2+ entry pathway into nonexcitable cells. Despite intensive investigation, mechanisms underlying activation of SOC entry have remained elusive. The endothelial I SOC channel is a Ca 2+ -selective SOC entry channel to which the transient receptor potential (TRP) proteins TRPC1 and TRPC4 contribute subunits. Activation of I SOC is specifically regulated by the spectrin–actin membrane skeleton; however, the nature of coupling between the I SOC channel and membrane skeleton is unknown. Here we demonstrate that protein 4.1 is an essential component of the I SOC channel gating mechanism. Protein 4.1 interacts with TRPC4 and the membrane skeleton. Deletion of the protein 4.1 binding domain on TRPC4 or peptide competition to the protein 4.1 binding domain prevents I SOC activation. These findings reveal that interaction of protein 4.1 with TRPC4 is required for activation of the endothelial I SOC channel.

Activation of the Endothelial Store-Operated ISOC Ca2+ Channel Requires Interaction of Protein 4.1 With TRPC4

On the endothelial cell ISOC

Rises in cytosolic calcium are sufficient to initiate the retraction of endothelial cell borders and to increase macromolecular permeability. Although endothelial cell biologists have recognized the importance of shifts in cytosolic calcium for several decades, only recently have we gained a rudimentary understanding of the membrane calcium channels that change cell shape. Members of the transient receptor potential family (TRP) are chief among the molecular candidates for permeability-coupled calcium channels. Activation of calcium entry through store-operated calcium entry channels, most notably TRPC1 and TRPC4, increases lung endothelial cell permeability, as does activation of calcium entry through the TRPV4 channel. However, TRPC1 and TRPC4 channels appear to influence the lung extraalveolar endothelial barrier most prominently, whereas TRPV4 channels appear to influence the lung capillary endothelial barrier most prominently. Thus, phenotypic heterogeneity in ion channel expression and function exists within the lung endothelium, along the arterial-capillary-venous axis, and is coupled to discrete control of endothelial barrier function.

Donna L. Cioffi

Papers

Host nutritional selenium status as a driving force for influenza virus mutations.

Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase.

Activation of the Endothelial Store-Operated ISOC Ca2+ Channel Requires Interaction of Protein 4.1 With TRPC4

On the endothelial cell ISOC

TRPing on the lung endothelium: calcium channels that regulate barrier function.