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Stroke Res."],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Canonical transient receptor potential (TRPC) non-selective cation channels, particularly those assembled with TRPC3, TRPC6, and TRPC7 subunits, are coupled to G<jats:sub>\u03b1q<\/jats:sub>-type G protein-coupled receptors for the major classes of excitatory neurotransmitters. Sustained activation of this TRPC channel-based pathophysiological signaling hub in neurons and glia likely contributes to prodigious excitotoxicity-driven secondary brain injury expansion. This was investigated in mouse models with selective <jats:italic>Trpc<\/jats:italic> gene knockout (KO). In adult cerebellar brain slices, application of glutamate and the class I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine to Purkinje neurons expressing the GCaMP5g Ca<jats:sup>2+<\/jats:sup> reporter demonstrated that the majority of the Ca<jats:sup>2+<\/jats:sup> loading in the molecular layer dendritic arbors was attributable to the TRPC3 effector channels (<jats:italic>Trpc3<\/jats:italic><jats:sup><jats:italic>KO<\/jats:italic><\/jats:sup> compared with wildtype (WT)). This Ca<jats:sup>2+<\/jats:sup> dysregulation was associated with glutamate excitotoxicity causing progressive disruption of the Purkinje cell dendrites (significantly abated in a <jats:italic>GAD67-GFP<\/jats:italic>-<jats:italic>Trpc3<\/jats:italic><jats:sup><jats:italic>KO<\/jats:italic><\/jats:sup> reporter brain slice model). Contribution of the G<jats:sub>\u03b1q<\/jats:sub>-coupled TRPC channels to secondary brain injury was evaluated in a dual photothrombotic focal ischemic injury model targeting cerebellar and cerebral cortex regions, comparing day 4 post-injury in WT mice, <jats:italic>Trpc3<\/jats:italic><jats:sup><jats:italic>KO<\/jats:italic><\/jats:sup>, and <jats:italic>Trpc1\/3\/6\/7<\/jats:italic> quadruple knockout (<jats:italic>Trpc<\/jats:italic><jats:sup><jats:italic>QKO<\/jats:italic><\/jats:sup>), with immediate 2-h (primary) brain injury. Neuroprotection to secondary brain injury was afforded in both brain regions by <jats:italic>Trpc3<\/jats:italic><jats:sup><jats:italic>KO<\/jats:italic><\/jats:sup> and <jats:italic>Trpc<\/jats:italic><jats:sup><jats:italic>QKO<\/jats:italic><\/jats:sup> models, with the <jats:italic>Trpc<\/jats:italic><jats:sup><jats:italic>QKO<\/jats:italic><\/jats:sup> showing greatest neuroprotection. These findings demonstrate the contribution of the G<jats:sub>\u03b1q<\/jats:sub>-coupled TRPC effector mechanism to excitotoxicity-based secondary brain injury expansion, which is a primary driver for mortality and morbidity in stroke, traumatic brain injury, and epilepsy.<\/jats:p>","DOI":"10.1007\/s12975-023-01173-1","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T05:01:43Z","timestamp":1689656503000},"page":"844-858","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["TRPC Channels Activated by G Protein-Coupled Receptors Drive Ca2+ Dysregulation Leading to Secondary Brain Injury in the Mouse Model"],"prefix":"10.1007","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0285-8698","authenticated-orcid":false,"given":"Jasneet","family":"Parmar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7423-3355","authenticated-orcid":false,"given":"Georg","family":"von Jonquieres","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4385-5271","authenticated-orcid":false,"given":"Nagarajesh","family":"Gorlamandala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7197-4369","authenticated-orcid":false,"given":"Amanda J.","family":"Craig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy L.","family":"Pinyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0775-8661","authenticated-orcid":false,"given":"Lutz","family":"Birnbaumer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0574-612X","authenticated-orcid":false,"given":"Matthias","family":"Klugmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7957-2498","authenticated-orcid":false,"given":"Andrew J.","family":"Moorhouse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2478-8416","authenticated-orcid":false,"given":"John M.","family":"Power","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8413-588X","authenticated-orcid":false,"given":"Gary D.","family":"Housley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"1173_CR1","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.ceca.2010.01.003","volume":"47","author":"K Szydlowska","year":"2010","unstructured":"Szydlowska K, Tymianski M. 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Dr. Jasneet Parmar is a fulltime employee of Nyrada Inc. Nyrada Inc is currently developing a small molecule inhibitor of TRPC ion channels. The experiments described here were conducted prior to their respective roles with Nyrada and were not funded by the Company. The TRPC channel target for brain injury neuroprotection has been declared in public statements by Nyrada Inc, which acknowledges GDH and UNSW. A patent filed on the block of TRPC3 channels for neuroprotection (AU2013286815B2; ceased) includes AJC, GDH, MK, AJM, JMP as inventors and UNSW as the assignee (NewSouth Innovations Pty Ltd).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}