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Store-Operated Ca Entry in Fibrosis and Tissue Remodeling.
Contact (Thousand Oaks)
December 2024
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Fibrosis is a pathological condition characterized by excessive tissue deposition of extracellular matrix (ECM) components, leading to scarring and impaired function across multiple organ systems. This complex process is mediated by a dynamic interplay between cell types, including myofibroblasts, fibroblasts, immune cells, epithelial cells, and endothelial cells, each contributing distinctively through various signaling pathways. Critical to the regulatory mechanisms involved in fibrosis is store-operated calcium entry (SOCE), a calcium entry pathway into the cytosol active at the endoplasmic reticulum-plasma membrane contact sites and common to all cells.
View Article and Find Full Text PDFGenetic evidence against involvement of TRPC proteins in SOCE, ROCE, and CRAC channel function.
Proc Natl Acad Sci U S A
December 2024
Institute of Biomedical Research, School of Biomedical Sciences, Catholic University of Argentina, Buenos Aires C1107AFF, Argentina.
Article Synopsis
- Researchers used genetically engineered mice and cell lines to study how the depletion of endoplasmic reticulum (ER) calcium stores activates specific calcium entry channels (SOCE) that primarily rely on Orai1 molecules.
- They discovered that Orai1 is the dominant calcium entry pathway compared to Orai2 and Orai3, and this process does not require functional TRPC molecules, as shown by experiments using cells with inactive TRPC genes.
- The study also found that even though the TRPC genes were disrupted, both store-depletion-activated calcium entry and receptor-operated calcium entry (ROCE) still relied on Orai1, leading to the establishment of a new strain of mice called TRPC heptaKO mice, which are
CRAC channels enable calcium entry from the extracellular space in response to a variety of stimuli and are crucial for gene expression and granule exocytosis in lymphocytes. Here we find that Syntaxin11, a Q-SNARE, associated with FHLH4 disease in human patients, directly binds Orai1, the pore forming subunit of CRAC channels. Syntaxin11 depletion strongly inhibited SOCE, CRAC currents, IL-2 expression and cytotoxicity in cell lines and FHLH4 patient T lymphocytes.
View Article and Find Full Text PDFDiscovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold.
Eur J Med Chem
November 2024
Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. Electronic address:
Article Synopsis
- The calcium release activated calcium (CRAC) channel is vital in T lymphocytes for regulating immune functions, including T cell activation and cytokine production.
- Mutations in CRAC channel components can lead to severe immune disorders like SCID and muscle diseases such as tubular aggregated myopathy (TAM).
- Recent studies identified compound 4k as a promising selective blocker of the CRAC channel, effectively inhibiting T cell activity while sparing other channels like TRPM4 and TRPM7, potentially offering a new approach for therapeutic interventions.
Extract Exerts Its Therapeutic Effect through CRAC Channel Inhibition for Atopic Dermatitis Treatment.
Int J Mol Sci
August 2024
Department of Physiology, Dongguk University College of Medicine, 123 Dongdae-ro, Gyeongju 38066, Gyeongsangbuk-do, Republic of Korea.
Atopic dermatitis (AD) is a common allergic inflammatory skin condition marked by severe itching, skin lichenification, and chronic inflammation. AD results from a complex immune response, primarily driven by T lymphocytes and environmental triggers, leading to a disrupted epidermal barrier function. Traditional treatments, such as topical corticosteroids, have limitations due to long-term side effects, highlighting the need for safer alternatives.
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