PR:000011406 PR glucocorticoid receptor CHEBI:29108 CHEBI calcium(2+) GO:0004883 GO glucocorticoid receptor activity VT:0010499 VT calcium amount 1 WIKI increased SSRI (Selective serotonin reuptake inhibitor) 2017-04-13T15:32:43 2017-04-13T15:32:43 Increase cortisone levels (induced by stress) 2017-04-14T14:34:24 2017-06-01T11:16:42 10116 NCBI Rattus norvegicus 9606 NCBI Homo sapiens Inhibit, serotonin transporter activity Molecular AOPWiki 2017-04-13T14:16:49 2017-04-13T14:16:49 Decreased, serotonin transporter activity Molecular AOPWiki 2017-04-13T14:17:16 2017-05-31T16:47:44 Decreased, extracellular Na+ Molecular AOPWiki 2017-04-13T14:18:45 2017-04-13T14:18:45 Decreased, extracellular chloride (Cl-) Molecular AOPWiki 2017-04-13T14:19:23 2017-04-13T14:19:23 Increased, extracellular serotonin Molecular AOPWiki 2017-04-13T14:20:14 2017-05-31T16:48:15 Increased, intracellular sodium (Na+) Molecular AOPWiki 2017-04-13T14:21:05 2017-04-13T14:21:05 Increased, intracellular chloride (Cl-) Molecular AOPWiki 2017-04-13T14:21:34 2017-04-13T14:21:34 Decreased, intracellular serotonin Molecular AOPWiki 2017-04-13T14:47:41 2017-05-31T16:47:24 Decreased, packaged serotonin Molecular AOPWiki 2017-04-13T14:48:44 2017-05-31T16:46:49 Decreased, synaptic release Molecular AOPWiki 2017-04-13T14:49:20 2017-05-31T16:46:28 Increased, 5-HT3 Molecular AOPWiki 2017-04-13T14:57:01 2017-06-01T14:48:51 Inactivated, 5-HTR Molecular AOPWiki 2017-04-13T14:59:07 2017-05-31T16:45:48 Reduce expression, BDNF Molecular AOPWiki 2017-04-13T15:00:03 2017-05-31T16:40:41 Decreased, neuroplasticity Molecular AOPWiki 2017-04-13T15:09:18 2017-05-31T16:45:25 Increase, cortisone Molecular AOPWiki 2017-04-13T15:14:07 2017-04-13T15:14:07 Activation, Glucocorticoid Receptor Molecular <p><strong>Site of action:</strong> The molecular site of action is the glucocorticoid receptor (GR). The GR is a steroid receptor belonging to the nuclear receptor (NR) family of ligand-dependent transcription factors. In the absence of a ligand, the GR is transcriptionally inactive in the cytoplasm. <strong>Responses at the macromolecular level:</strong> Binding of a hormonal ligand enables GR to translocate into the nucleas where it binds to genomic GC-response elements (GRE) and regulates trascription of associated genes.</p> <p>Glucocorticoid activation can be measured in a number of assays as stated by the EPA&rsquo;s comptox dashboard (<a href="https://comptox.epa.gov/dashboard/assay_endpoints?search=NR3C1">https://comptox.epa.gov/dashboard/assay_endpoints?search=NR3C1</a>).</p> <ul> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/ATG_GRE_CIS_up">ATG_GRE_CIS_up</a></li> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/ATG_GR_TRANS_up">ATG_GR_TRANS_up</a></li> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/NVS_NR_hGR">NVS_NR_hGR</a></li> <li><a href="https://comptox.epa.gov/dashboard/assay_endpoints/TOX21_GR_BLA_Agonist_ratio">TOX21_GR_BLA_Agonist_ratio</a></li> </ul> <p>Receptor Transactivation Assays:</p> <ul> <li>Indigo Biosciences Human GR reporter assay system. Product Family IB0020 GR</li> <li>Androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening of surface water samples (Hartig et al, 2002).</li> </ul> <p>In addition to invitro assay, induction of glucocorticoid receptor-regulated genes such as annexin a1b, gilz, glula, and fkbp1 are also indicative of GR activation in vivo (Garland et al., 2019).</p> <p>Glucocorticoid receptor is fairly conserved across vertebrates. Fish however, have two copies of the gene resulting in two different receptors. Although conserved across species, the sensitivity of the glucocorticoid receptor varies based on species (Solte et al., 2006).</p> <p>&nbsp;</p> CL:0000255 CL eukaryotic cell Moderate Mixed Moderate All life stages <p style="margin-left:0.5in">Garland MA, Sengupta S, Mathew LK, Truong L, Jong ED, Piersma AH, Du JL, Tanguay RL. 2019. <em>Glucocorticoid receptor-dependent induction of </em>cripto-1<em> (one-eyed pinhead) inhibits zebrafish caudal fin regeneration. </em>Toxicology Reports 6:529-537. https://doi.org/10.1016/j.toxrep.2019.05.013</p> <p style="margin-left:0.5in">Solte EH, Lidy Verberg van Kemenade BM, Savelkoul FJ, Flik G. 2006. <em>Evolution of glucocorticoid receptors with different glucocorticoid sensitivity.</em> Journal of Endocrinology 190:17-28. DOI: 10.1677/joe.1.06703</p> <p style="margin-left:0.5in">Medlock Kakaley EK, Blackwell BR, Cardon MC, Conley JM, Evans N, Feifarek DJ, Furlong ET, Glassmeyer ST, Gray LE Jr, Hartig PC, Kolpin DW, Mills MA, Rosenblum L, Villeneuve DL, Wilson VS. <em>De Facto Water Reuse: Bioassay suite approach delivers depth and breadth in endocrine active compound detection</em>. Sci Total Environ. 2020 Jan 10;699:134297. doi: 10.1016/j.scitotenv.2019.134297. Epub 2019 Sep 4. PubMed PMID: 31683213.</p> <p>Conley JM, Lambright CS, Evans N, Strynar MJ, McCord J, McIntyre BS, Travlos GS, Cardon MC, Medlock-Kakaley E, Hartig PC, Wilson VS, Gray LE Jr. <em>Adverse Maternal, Fetal, and Postnatal Effects of Hexafluoropropylene Oxide Dimer Acid (GenX) from Oral Gestational Exposure in Sprague-Dawley Rats. Environ Health Perspect</em>. 2019 Mar;127(3):37008. doi: 10.1289/EHP4372. PubMed PMID: 30920876;PubMed Central PMCID: PMC6768323.</p> <p>Medlock Kakaley E, Cardon MC, Gray LE, Hartig PC, Wilson VS. <em>Generalized Concentration Addition Model Predicts Glucocorticoid Activity Bioassay Responses to Environmentally Detected Receptor-Ligand Mixtures</em>. Toxicol Sci. 2019 Mar 1;168(1):252-263. doi: 10.1093/toxsci/kfy290. PubMed PMID: 30535411; PubMed Central PMCID: PMC6709530.&nbsp;</p> <p>Conley JM, Evans N, Cardon MC, Rosenblum L, Iwanowicz LR, Hartig PC, Schenck KM, Bradley PM, Wilson VS. <em>Occurrence and In Vitro Bioactivity of Estrogen, Androgen, and Glucocorticoid Compounds in a Nationwide Screen of United States Stream Waters</em>. Environ Sci Technol. 2017 May 2;51(9):4781-4791. doi:10.1021/acs.est.6b06515. Epub 2017 Apr 12. PubMed PMID: 28401766.&nbsp;</p> <p>Hartig PC, Bobseine KL, Britt BH, Cardon MC, Lambright CR, Wilson VS, Gray LE Jr. <em>Development of two androgen receptor assays using adenoviral transduction of MMTV-luc reporter and/or hAR for endocrine screening</em>. Toxicol Sci. 2002 Mar;66(1):82-90. PubMed PMID: 11861975.</p> <p>&nbsp;</p> AOPWiki 2016-11-29T18:41:22 2020-07-07T12:19:59 Reduced, BDNF Molecular AOPWiki 2017-04-13T15:15:22 2017-05-31T17:30:16 Activation, 5-HT2A Molecular AOPWiki 2017-04-13T15:25:34 2017-04-13T15:25:34 Activate, PLC Molecular AOPWiki 2017-04-13T15:26:24 2017-04-13T15:26:24 Increase, inositol triphosphate Molecular AOPWiki 2017-04-13T15:27:05 2017-04-13T15:27:05 Increase, intracellular calcium Cellular <p>Calcium is arguably the most versatile and important intracellular messenger in neurons<span style="font-size:12pt"><span style="font-family:&quot;Times New Roman&quot;,serif"> </span></span>(Berridge et al., 2000). Interestingly, although calcium may often promote neuronal death, it can also activate pathways that promote survival. For example, calcium can promote survival through a pathway involving activation of protein kinase B (PKB/Akt) by calcium/calmodulin-dependent protein kinase&nbsp;(Yano et al., 1998). Calcium is a prominent regulator of cellular responses to stress, activating transcription through the cyclic-AMP response element-binding protein (CREB), which can promote neuron survival in experimental models of developmental cell death&nbsp;(Hu et al., 1999). Calcium can also activate a rapid neuroprotective signalling pathway in which the calcium-activated actin-severing protein gelsolin induces actin depolymerization, resulting in suppression of calcium influx through membrane NMDA (N-methyl-d-aspartate) receptors and voltage-dependent calcium channels&nbsp;(Furukawa et al., 1997). This may occur through intermediary actin-binding proteins that interact with NMDA receptor and calcium channel proteins. Finally, signals such as calcium and secreted amyloid precursor protein-&alpha; (sAPP-&alpha;), which increase cyclic GMP production, can induce activation of potassium channels and the transcription factor NF-&kappa;B, and thereby increase resistance of neurons to excitotoxic apoptosis&nbsp;(Furukawa et al., 1996).</p> <p>An increase in [Ca^2+]i was measured using Fluo3 AM as an indicator dye after the addition of metals (single or in mixture) to the culture wells following an optimized protocol&nbsp;(Arey et al., 2022). The fluorescent signals were read by fluorescence imaging plate reader Synergy HT (BioTek, Winooski, VT)&nbsp;(Rai and others 2010).</p> <p>Briefly, Ca2+ levels in human astrocytes were monitored by fluorescence microscopy using the Ca2+ indicator fluo-4. Slices were incubated with fluo-4-AM (2&ndash;5 &micro;L of 2 mM dye were dropped over the tissue, attaining a final concentration of 2&ndash;10 &micro;M and 0.01% of pluronic) and Sulforhodamine 101 (100 &micro;M) for 30&ndash;60 min at room temperature&nbsp;(Navarrete and others 2013). In these conditions, most of the Fluo-4-loaded cells were astrocytes as indicated by their SR101 staining (Nimmerjahn et al., 2004; Dombeck et al., 2007; Kafitz et al., 2008; Takata and Hirase 2008), and confirmed in some cases by their electrophysiological properties. Astrocytes were imaged with an Olympus FV300 laser-scanning confocal microscope or a CCD camera (Retiga EX) attached to the Olympus BX50WI microscope (Navarrete and others 2013).</p> <p>Diversity of endogenous Ca2+ activity in a mature hippocampal astrocyte in situ: Ca2+ signals in cell body and processes are different. (A) Cumulative Ca2+ activity recorded in an astrocyte over a 165 s period revealed by the calcium indicator Fluo4-AM. The visible boundaries of the astrocyte are shown in white. Note the different intensities of spatially-<br /> confined local activity in the astrocyte cell body (s), primary process (p1) stemming from the soma and secondary processes (p2) branching from a primary process. Intensity of the<br /> normalized cumulative activity is expressed in arbitrary units (a.u.) and shown in pseudocolour, from dark (lowest) to white (highest). (B) Frequency map of the Ca2+ activity in the astrocyte during the 165 s period as in A. Activity is measured in individual pixels, expressed in mHz and color-coded from black (never active) to dark red (frequently active). Most of the activity is within the white boundaries and the most frequently active pixels are in defined small regions (arrowheads) of the primary and secondary processes (30 mHz), whereas pixels of the soma are less active (~10 mHz) (Volterra et al., 2014).&nbsp;</p> <p>Free intracellular calcium ions were measured using the fluorescent calcium indicator FLUO-3/AM (Molecular probes, Eugene, OR, USA). Cells (4&nbsp;&times;&nbsp;10⁴&nbsp;cells/cm²) were seeded in 24-well plates for 24&nbsp;h to reach 60%&ndash;70%, and then treated for 24&nbsp;h with As(III) (0.5 and 1&nbsp;mg/l), or coexposed to As(III) (1&nbsp;mg/l) and F (2.5, 5, and 10&nbsp;mg/l). After treatment, supernatant was collected and combined with trypsinized cells. Pelleted samples were resuspended in 500&nbsp;&mu;l of FLUO-3/AM (4&nbsp;&mu;mol/l) and incubated at 37&nbsp;&deg;C for 30&nbsp;min. After centrifugation, cells were washed with HBSS (Hank&#39;s Buffered Salt Solution, Sigma), made up to 400&nbsp;&mu;l with HBSS and analyzed by flow cytometry. The signal from FLUO-3/AM bound to Ca²⁺ was recorded using the Fl-1 channel&nbsp;(Rocha et al., 2011).</p> <p>Fluo-4/AM was used as an intracellular free Ca²⁺ fluorescent probe to analyze [Ca²⁺]_i in Cd-exposed cerebral cortical neurons. In short, the harvested cells were incubated with Fluo-4/AM (5 &micro;mol/L final concentration) for 30 min at 37&deg;C in the dark, washed with PBS, and analyzed on a BD-FACS Aria flow cytometry. Intracellular [Ca²⁺]_i levels were represented by fluorescent intensity. Fluorescent intensity was recorded by excitation at 494 nm and emission at 516 nm. The data were analyzed by Cell Quest program (Becton Dickinson), and the mean fluorescence intensity was obtained by histogram statistics (Yuan et al., 2013).</p> UBERON:0000955 UBERON brain CL:0000000 CL cell Moderate Mixed Moderate Adult, reproductively mature Moderate Birth to < 1 month Moderate Moderate <p>Arey BJ Seethala R Ma Z Fura A Morin J Swartz J Vyas V Yang W Dickson JK JrFeyen JH A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo Endocrinology 2005 146 2015 2022</p> <p>Asit Rai and others, Characterization of Developmental Neurotoxicity of As, Cd, and Pb Mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions, Toxicological Sciences, Volume 118, Issue 2, December 2010, Pages 586&ndash;601, https://doi.org/10.1093/toxsci/kfq266</p> <p>Berridge, M. J., Lipp, P. &amp; Bootman, M. D. The versatility and universality of calcium signaling. Nature Rev. Mol. Cell Biol. 1, 11&ndash; 21 (2000).</p> <p>Dombeck DA, Khabbaz AN, Collman F, Adelman TL, Tank DW. Imaging large-scale neural activity with cellular resolution in awake, mobile mice, Neuron, 2007, vol. 56 (pg. 43-57)</p> <p>Furukawa, K. et al. The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J. Neurosci. 17, 8178&ndash; 8186 (1997).</p> <p>Furukawa, K., Barger, S. W., Blalock, E. M. &amp; Mattson, M. P. Activation of K+ channels and suppression of neuronal activity by secreted &beta;-amyloid-precursor protein. Nature 379, 74&ndash;78 (1996).</p> <p>Hu, S. C., Chrivia, J. &amp; Ghosh, A. Regulation of CBP-mediated transcription by neuronal calcium signaling. Neuron 22, 799&ndash; 808 (1999).</p> <p>Kafitz KW, Meier SD, Stephan J, Rose CR. Developmental profile and properties of sulforhodamine 101-labeled glial cells in acute brain slices of rat hippocampus, J Neurosci Methods, 2008, vol. 169 (pg. 84-92)</p> <p>Marta Navarrete and others, Astrocyte Calcium Signal and Gliotransmission in Human Brain Tissue, Cerebral Cortex, Volume 23, Issue 5, May 2013, Pages 1240&ndash;1246, https://doi.org/10.1093/cercor/bhs122</p> <p>Nimmerjahn A, Kirchhoff F, Kerr JN, Helmchen F. Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo, Nat Methods, 2004, vol. 1 (pg. 31-37)</p> <p>R.A. Rocha, J.V. Gimeno-Alca&ntilde;iz, R. Mart&iacute;n-Iba&ntilde;ez, J.M. Canals, D. V&eacute;lez, V. Devesa, Arsenic and fluoride induce neural progenitor cell apoptosis, Toxicology Letters, Volume 203, Issue 3, 2011, Pages 237-244, ISSN 0378-4274, https://doi.org/10.1016/j.toxlet.2011.03.023.</p> <p>Takata N, Hirase H. Cortical layer 1 and layer 2/3 astrocytes exhibit distinct calcium dynamics in vivo., PLoS ONE, 2008, vol. 3 pg. e2525</p> <p>Volterra, Andrea, Nicolas Liaudet, and Iaroslav Savtchouk. &quot;Astrocyte Ca2+ signalling: an unexpected complexity.&quot; Nature Reviews Neuroscience 15.5 (2014): 327-335.</p> <p>Yano, S., Tokumitsu, H. &amp; Soderling, T. R. Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. Nature 396, 584&ndash;587 (1998).</p> <p>Yuan Y, Jiang C-y, Xu H, Sun Y, Hu F-f, Bian J-c, et al. (2013) Cadmium-Induced Apoptosis in Primary Rat Cerebral Cortical Neurons Culture Is Mediated by a Calcium Signaling Pathway. PLoS ONE 8(5): e64330. https://doi.org/10.1371/journal.pone.0064330</p> AOPWiki 2017-04-13T15:27:51 2023-07-21T16:26:34 Activate, calmodulin Molecular AOPWiki 2017-04-13T15:28:30 2017-04-13T15:28:30 Increase, myosin light chain phosphorylation Molecular AOPWiki 2017-04-13T15:29:22 2017-04-13T15:29:22 Increase, vascular smooth muscle contraction Molecular AOPWiki 2017-04-13T15:30:06 2017-04-13T15:30:06 Increased, seizure Individual AOPWiki 2017-04-13T15:35:33 2017-06-01T11:55:50 Increased, agitation Molecular AOPWiki 2017-04-13T15:36:15 2017-06-01T11:35:55 Increased, depression Individual AOPWiki 2017-04-13T15:36:41 2017-06-01T16:06:02 Increase, hypertension Individual AOPWiki 2017-04-13T15:30:37 2017-04-13T15:30:37 Decreased, extracellular serotonin Molecular AOPWiki 2017-04-14T14:38:23 2017-05-31T16:46:08 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00005eb8a30b8be0> AOPWiki 2017-04-14T14:44:31 2017-04-14T14:44:31 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#<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc55ccf0> AOPWiki 2017-04-14T14:51:51 2017-04-14T14:51:51 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc59cc60> AOPWiki 2017-04-14T14:52:12 2017-04-14T14:52:12 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc60d3e8> AOPWiki 2017-04-14T14:52:36 2017-04-14T14:52:36 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b42fc70a610> AOPWiki 2017-04-14T14:53:03 2017-04-14T14:53:03 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b430040a9c0> AOPWiki 2017-04-14T14:53:31 2017-04-14T14:53:31 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43002386b0> AOPWiki 2017-04-14T14:54:04 2017-04-14T14:54:04 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43001fc070> AOPWiki 2017-04-14T14:54:31 2017-04-14T14:54:31 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43005840d0> AOPWiki 2017-04-14T14:55:00 2017-04-14T14:55:00 #<Reference::ActiveRecord_Associations_CollectionProxy:0x00007b43005d37c0> AOPWiki 2017-04-14T14:55:18 2017-04-14T14:55:18 Network of SSRIs Agnes Aggy Open for adoption 1.0 adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not Specified Not Specified adjacent Not 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