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Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
The intracellular Ca2+ concentration in lymphocytes (B and T cells) is around 50–100 nM, which upon antigenic stimulation can rise to 1 µM3. Ca2+ influx upon antigenic stimulation activates phospholipase C, resulting in the generation of inositol triphosphate 3 (IP3), which further potentiates the release of Ca2+ from the endoplasmic reticulum (ER)3. The ER Ca2+ release triggers Ca2+ influx across the plasma membrane through CRAC channels. This whole process is termed store-operated calcium entry (SOCE), which plays a central role in maintaining cellular Ca2+ homeostasis3,32. The major players in SOCE are ER Ca2+ sensor stromal interaction molecule 1 (STIM1) and STIM2 proteins and their interaction with plasma membrane CRAC channel component ORAI3. STIM1 is a single-pass transmembrane protein comprising ER Ca2+-sensing EF-hand motif and multiple protein-protein interaction motifs33. There are three homologs of ORAI – ORAI1, ORAI2, and ORAI3 – which form Ca2+ channels but differ in their pharmacological properties, tissue expression, and inactivation kinetics3,34.
Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
IP3 has been clearly identified as the second messenger for receptor-mediated release of intracellular Ca2+ from the sarcoplasmic reticulum (SR). Ca2+ is not released from the mitochondrial pool. The target is an IP3 receptor which forms the Ca2+ channel spanning the membrane of the intracellular SR Ca2+ storage site. At least three separate IP3 receptor genes have now been identified. Both IP3-sensitive and IPj-insensitive stores have been identified. The release of intracellular Ca2+ Uien initiates contractile responses of smooth muscle arising from a1- or M3 receptor stimulation and secretory responses such as enzyme secretion from the parotid salivary gland. The emptying of the intracellular Ca2+ pool by IP3 may also trigger the influx of Ca2+ through sarcolemma membrane Ca2+ channels, as has been described recently for mast cells and other cell lines. The process of Ca2+ influx is said to be via a Ca2+-release-activated channel (CRAC) and the current that flows through this channel is ICRAC Ca2+ influx via the CRAC does not necessarily require receptor occupancy, but can be triggered by other drugs or procedures that in common empty the intracellular Ca2+ stores. For example, the Ca2+ transporting ATPase inhibitor, thapsigargin, empties Ca2+ stores and causes elevated intracellular Ca2+ levels that are dependent upon extracellular Ca2+. The possible link between the emptying of the SR by IP3 receptor activation and Ca2+ influx via CRAC is a Ca2+ influx factor (CIF) released from the SR (Fasolato et al. 1994). The intracellular pool is subsequently replenished from the Ca2+ entering via Ca2+ influx. In addition to the IP3 receptor mediating Ca2+ release from the SR, ryanodine receptors are also present. Ryanodine activates the release of Ca2+ from the intracellular stores and at higher concentrations (>10 μM) inhibits the release. Caffeine also activates this receptor and induces smooth muscle contraction (Ehrlich et al. 1994).
Roles of CRAC channel in cancer: implications for therapeutic development
Published in Expert Review of Precision Medicine and Drug Development, 2020
Husain Yar Khan, Iqra Mazahir, Shriya Reddy, Farzeen Fazili, Asfar Sohail Azmi
CRAC channel regulates intracellular Ca2+ homeostasis in nonexcitable cells through mediating SOCE which is triggered in response to depletion of Ca2+ from the endoplasmic reticulum stores. STIM proteins sense the loss of Ca2+ from endoplasmic reticulum and their subsequent coupling with plasma membrane bound Orai proteins forms a functional CRAC channel that allows the influx of Ca2+ into the cell. The critical role of CRAC channel mediated Ca2+ entry in promoting cell proliferation, cell cycle progression, resistance to apoptosis, invasion, and metastasis in several types of cancers has been demonstrated in numerous independent studies. Moreover, there is ample evidence that the expression of CRAC channel proteins, Orai and STIM, is upregulated in various types of cancer cells and patient tumor tissues as compared to normal cells and noncancerous tissue samples, respectively.
Differential expression of CRAC channel in alloxan induced Diabetic BALB/c mice
Published in Immunopharmacology and Immunotoxicology, 2020
Anantha Maharasi Ramakrishnan, Pavitra Kumar, Suvro Chatterjee, Kavitha Sankaranarayanan
As mentioned earlier CRAC channels play an inevitable role in the development of autoimmune disease like MS and RA [9,11]. We have identified upregulated expression of CRAC channel components like STIM1, ORAI1, ORAI2 and pro-inflammatory cytokines like IL-1β and TNF-α in the T cells isolated from 12 and 24 h of alloxan-treated diabetic BALB/c mice. In addition to that, we have observed increased intracellular calcium level in T cells of alloxan induced T1D mice which has been likely involved in the activation of lymphocyte, immune responses and cytokine production [57–59]. Serum concentrations of IL-1β and TNF-α in T1D subjects have been increased compared to healthy control[1,60]. The combinations of these cytokines at low concentrations, like 10 and 100 U/mL, cause apoptosis and necrosis of the pancreatic β islets by binding to the specialized receptor for instance, IL-1β and TNF-α bind to the IL-1Receptor and TNF receptor, respectively. Upon stimulation with these cytokines, there are a number of genes have been upregulated like Caspases, iNOS, and many of them down regulated which includes anti-apoptosis gene Bcl-2 [54,60] in the pancreatic islets that finally leads to pancreatic β cell destruction. Therefore, we are imposing that upregulating expression of CRAC channels responsible for the increased cytokine production in T cells and which attribute for the pancreatic β cell destruction in T1D.
Boron’s neurophysiological effects and tumoricidal activity on glioblastoma cells with implications for clinical treatment
Published in International Journal of Neuroscience, 2019
Meric A. Altinoz, Gulacti Topcu, İlhan Elmaci
Increase of intracellular Ca2+ via Ca2+ influx involve in transcription of genes, progression of the cell-cycle and apoptotic cell death [71]. The influx of calcium can be triggered by receptor activation (receptor-operated calcium entry, ROCE), or through depleting stores of the internal calcium within the endoplasmic reticulum (store-operated calcium entry (SOCE)) [71]. CRAC channels are mostly investigated SOCE pathways. CRAC channels are formed by minimum two components: ORAI1, a pore protein residing on the plasma membrane and STIM1, a calcium sensor protein STIM1 in the endoplasmic reticulum (ER). STIM1 can sense depletion of ER Ca2+ stores and triggers the activation of ORAI1 to perform store-operated Ca2+ entry [71]. CRAC inhibition suppresses cancer cell growth by blocking cell cycle and inhibits metastasis in breast and prostate cancer models. C6 cell proliferation is significantly inhibited by silencing the expression of ORAI1 and STIM1 proteins using siRNA [71]. SKF-96365 and 2-APB also inhibited cell proliferation and SOCE in glioblastoma cells and increased apoptosis in C6 glioblastoma cells [71].