https://www.cell.com/cell/pdf/S0092-8674(09)01243-4.pdf

Cellular and Molecular Mechanisms of Pain

Persistent postsurgical pain: risk factors and prevention

Microglial cells are the resident macrophages in the central nervous system. These cells of mesodermal/mesenchymal origin migrate into all regions of the central nervous system, disseminate through the brain parenchyma, and acquire a specific ramified morphological phenotype termed "resting microglia." Recent studies indicate that even in the normal brain, microglia have highly motile processes by which they scan their territorial domains. By a large number of signaling pathways they can communicate with macroglial cells and neurons and with cells of the immune system. Likewise, microglial cells express receptors classically described for brain-specific communication such as neurotransmitter receptors and those first discovered as immune cell-specific such as for cytokines. Microglial cells are considered the most susceptible sensors of brain pathology. Upon any detection of signs for brain lesions or nervous system dysfunction, microglial cells undergo a complex, multistage activation process that converts them into the "activated microglial cell." This cell form has the capacity to release a large number of substances that can act detrimental or beneficial for the surrounding cells. Activated microglial cells can migrate to the site of injury, proliferate, and phagocytose cells and cellular compartments.

Physiology of Microglia

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 family of voltage-gated sodium channels initiates action potentials in all types of excitable cells. Nine members of the voltage-gated sodium channel family have been characterized in mammals, and a 10th member has been recognized as a related protein. These distinct sodium channels have similar structural and functional properties, but they initiate action potentials in different cell types and have distinct regulatory and pharmacological properties. This article presents the molecular relationships and physiological roles of these sodium channel proteins and provides comprehensive information on their molecular, genetic, physiological, and pharmacological properties.

https://pharmrev.aspetjournals.org/content/pharmrev/57/4/411.full.pdf

International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels

T cell activation and function depend on Ca2+ signals mediated by store-operated Ca2+ entry (SOCE) through Ca2+ release–activated Ca2+ (CRAC) channels formed by ORAI1 proteins. We here investigated how SOCE controls T cell function in pulmonary inflammation during a T helper 1 (TH1) cell–mediated response to influenza A virus (IAV) infection and TH2 cell–mediated allergic airway inflammation. T cell–specific deletion of Orai1 did not exacerbate pulmonary inflammation and viral burdens following IAV infection but protected mice from house dust mite–induced allergic airway inflammation. ORAI1 controlled the expression of genes including p53 and E2F transcription factors that regulate the cell cycle in TH2 cells in response to allergen stimulation and the expression of transcription factors and cytokines that regulate TH2 cell function. Systemic application of a CRAC channel blocker suppressed allergic airway inflammation without compromising immunity to IAV infection, suggesting that inhibition of SOCE is a potential treatment for allergic airway disease.

https://www.science.org/doi/pdf/10.1126/sciadv.abn6552?download=true

Distinct roles of ORAI1 in T cell–mediated allergic airway inflammation and immunity to influenza A virus infection

L'invention concerne des composes, et des compositions pharmaceutiques contenant de tels composes, qui modulent l'activite de canaux calciques capacitifs (SOC) L'invention concerne egalement des procedes pour utiliser de tels modulateurs de canal SOC, seuls ou en combinaison avec d'autres composes, pour traiter des maladies, des troubles ou des etats qui beneficieraient d'une inhibition de l'activite de canal SOC

Inhibiteurs benzylthiotétrazole de libération de calcium capacitif

L’invention concerne des composes et des compositions pharmaceutiques contenant de tels composes permettant de moduler l’activite des canaux calciques actives par les reserves intracellulaires (SOC). L’invention porte egalement sur des procedes d’utilisation desdits modulateurs du canal SOC, seuls ou en combinaison avec d’autres composes, dans le cadre du traitement de maladies ou conditions pour lesquelles l’inhibition de l’activite du canal SOC se revelerait benefique.

Composés modulant le calcium intracellulaire

FIELD: chemistry.SUBSTANCE: invention relates to compounds of formula (I):where: A, J, R1, R4, X, Z are given in claim 1, and to a pharmaceutical composition containing such compounds, which modulate activity of store-operated calcium (SOC) channels. The present invention also describes methods of using such SOC channel modulators to treat diseases or conditions where inhibition of activity of SOC channels can be beneficial.EFFECT: improved method.17 cl, 5 tbl, 2 dwg, 8 ex

Intracellular calcium modulating compounds

Patients with recurrent acute pancreatitis (RAP) are at significant risk of developing early chronic pancreatitis (CP), which progresses into irreversible, end-stage CP with severe symptoms. There is no specific therapy in RAP or in early CP that may hinder disease progression. The pathogenesis of CP is complex and involves interactions among multiple cell types, including pancreatic acinar, ductal, and stellate cells (PSC). Therefore, it is pivotal to identify common pathogenic pathways in these cells that could be targeted pharmacologically. The Orai1-mediated store-operated Ca2+ entry (SOCE) is a ubiquitous signaling mechanism, which may become overactivated in pathological states resulting intracellular Ca2+ overload. In this study, we used ex vivo and in vivo preclinical disease models to demonstrate that Orai1 inhibition prevents progression of RAP and early CP. The selective Orai1 inhibitor CM5480 restored the expression of SOCE-associated regulatory factor in acinar cells, prevented uncontrolled Ca2+ elevation, protected acinar and ductal functions, mitigated immune cell infiltration, and diminished PSC activation, proliferation and migration. We suggest that the overactivation of Orai1 is a crucial pathogenetic event in the progression of early CP, and inhibition of Orai1 could prevent the development of end-stage CP.

http://insight.jci.org/articles/view/167645/files/pdf

Kenneth A. Stauderman

Papers

Distinct roles of ORAI1 in T cell–mediated allergic airway inflammation and immunity to influenza A virus infection

Inhibiteurs benzylthiotétrazole de libération de calcium capacitif

Composés modulant le calcium intracellulaire

Intracellular calcium modulating compounds

Orai1 calcium channel inhibition prevents progression of chronic pancreatitis.