{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:03:16Z","timestamp":1790701396502,"version":"4.1.0"},"reference-count":12,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University John Anderson Research Award (JARA) Studentship"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Integr. Neurosci."],"abstract":"<jats:p>Background: Protease-activated receptors are G protein-coupled receptors with a novel activation mechanism by which proteases cleave the N-terminus revealing a tethered ligand that binds to the second extracellular loop leading to receptor activation. We have previously shown that protease-activated receptor 2 (PAR2) activation impairs hippocampal synaptic transmission and is neuroprotective in in vitro excitotoxic assays, both of which are astrocyte-dependent. We have also shown that AC264613, a blood-brain barrier-permeable PAR2 activator, results in behavioural changes associated with depression-like behaviour and recently revealed that AC264613 reduces astrocyte reactivity and amyloid load in a mouse model of amyloid pathology. However, whether functional protease-activated receptors are present in human astrocytes and if they alter their reactivity state is unknown. Methods: Commercially available human astrocytes were cultured in serum and serum-free media, and the presence of functional PARs was investigated using standard Ca2+ imaging techniques. Immunocytochemistry was used to examine the consequence of PAR activation on their reactive phenotype. Results: We reveal that functional PAR1 and PAR2 are present in commercially available human astrocytes. Their activation increased glial fibrillary acidic protein (GFAP) expression only after short-term culture but did not affect complement component 3 (C3) or guanylate-binding protein 2 (Gbp2) expression under any conditions tested. In contrast, no change in reactivity was observed following exposure to inflammatory stimuli. Conclusion: Overall, these data highlight that human astrocytes express functional PARs, but their activation may result in different phenotypic changes from those seen in mouse astrocytes.<\/jats:p>","DOI":"10.31083\/jin55298","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:16:31Z","timestamp":1790698591000},"source":"Crossref","is-referenced-by-count":0,"title":["Human Astrocytes Express Functional Protease-Activated Receptors that Increase Their Reactive Phenotype Under Certain Culture Conditions"],"prefix":"10.31083","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-0163-8399","authenticated-orcid":true,"given":"Aparna","family":"Maruvada","sequence":"first","affiliation":[{"name":"Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, G4 0RE Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4145-9670","authenticated-orcid":true,"given":"Trevor J","family":"Bushell","sequence":"additional","affiliation":[{"name":"Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, G4 0RE Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Xu Z, Li R, Zhang J. Unravelling Structure-Based Molecular Activation and Antagonism of Protease-Activated Receptors for Drug Design. Medicinal Research Reviews. 2026; 46: 1051\u20131070.","DOI":"10.1002\/med.70048"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Almonte AG, Qadri LH, Sultan FA, Watson JA, Mount DJ, Rumbaugh G, et al. Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity. Journal of Neurochemistry. 2013; 124: 109\u2013122.","DOI":"10.1111\/jnc.12075"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Kim HN, Triplet EM, Radulovic M, Bouchal S, Kleppe LS, Simon WL, et al. The thrombin receptor modulates astroglia-neuron trophic coupling and neural repair after spinal cord injury. Glia. 2021; 69: 2111\u20132132.","DOI":"10.1002\/glia.24012"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Moudio S, Willis A, Pytka K, Abulkassim R, Brett RR, Webster JF, et al. Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines. Psychopharmacology. 2022; 239: 229\u2013242.","DOI":"10.1007\/s00213-021-06040-1"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Edwards N, Sakata S, McConnell G, Bushell TJ. Astrocytic reactivity and amyloid load are reduced in a sex-dependent manner in a mouse model of amyloid pathology following protease-activated receptor 2 activation. Neuropharmacology. 2026; 297: 111010.","DOI":"10.1016\/j.neuropharm.2026.111010"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Peach CJ, Edgington-Mitchell LE, Bunnett NW, Schmidt BL. Protease-activated receptors in health and disease. Physiological Reviews. 2023; 103: 717\u2013785.","DOI":"10.1152\/physrev.00044.2021"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Pompili E, Fabrizi C, Fornai F, Fumagalli L. Role of the protease-activated receptor 1 in regulating the function of glial cells within central and peripheral nervous system. Journal of Neural Transmission (Vienna, Austria : 1996). 2019; 126: 1259\u20131271.","DOI":"10.1007\/s00702-019-02075-z"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Lopez DM, Keavey LK, Bowles KR. Using iPSC models to examine neuron-glia interactions in neurodegenerative diseases. Bioscience Reports. 2026; 46: BSR20250131.","DOI":"10.1042\/BSR20250131"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Liddelow SA. Modern approaches to investigating non-neuronal aspects of Alzheimer's disease. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2019; 33: 1528\u20131535.","DOI":"10.1096\/fj.201802592"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"White KE, Bailey HL, Shaw BS, Geiszler PC, Mesquita-Ribeiro R, Scott D, et al. A convenient model of serum-induced reactivity of human astrocytes to investigate astrocyte-derived extracellular vesicles. Frontiers in Cellular Neuroscience. 2024; 18: 1414142.","DOI":"10.3389\/fncel.2024.1414142"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Prah J, Winters A, Chaudhari K, Hersh J, Liu R, Yang SH. A novel serum free primary astrocyte culture method that mimic quiescent astrocyte phenotype. Journal of Neuroscience Methods. 2019; 320: 50\u201363.","DOI":"10.1016\/j.jneumeth.2019.03.013"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Kousa I, Talvio K, Peteri UK, Castr\u00e9n ML. Special characteristics of human astrocytes and their roles in brain homeostasis. 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