{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T15:17:06Z","timestamp":1778253426454,"version":"3.51.4"},"reference-count":70,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,6,27]],"date-time":"2012-06-27T00:00:00Z","timestamp":1340755200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2012,7]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold>3\u2010Hydroxy\u2010octanoate, recently identified as a ligand for, the orphan GPCR, HCA<jats:sub>3<\/jats:sub>, is of particular interest given its ability to treat lipid disorders and atherosclerosis. Here we demonstrate the pathway of HCA<jats:sub>3<\/jats:sub>\u2010mediated activation of ERK1\/2.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold>Using CHO\u2010K1 cells stably expressing HCA<jats:sub>3<\/jats:sub>receptors and A431 cells, a human epidermoid cell line with high levels of endogenous expression of functional HCA<jats:sub>3<\/jats:sub>receptors, HCA<jats:sub>3<\/jats:sub>\u2010mediated activation of ERK1\/2 was measured by Western blot.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold>HCA<jats:sub>3<\/jats:sub>\u2010mediated activation of ERK1\/2 was rapid, peaking at 5\u2003min, and was<jats:italic>Pertussis<\/jats:italic>toxin sensitive. Our data, obtained by time course analyses in combination with different kinase inhibitors, demonstrated that on agonist stimulation, HCA<jats:sub>3<\/jats:sub>receptors evoked ERK1\/2 activation via two distinct pathways, the PLC\/PKC pathway at early time points (\u22642\u2003min) and the MMP\/ epidermal growth factor receptor (EGFR) transactivation pathway with a maximum response at 5\u2003min. Furthermore, our present results also indicated that the \u03b2\u03b3\u2010subunits of the G<jats:sub>i<\/jats:sub>protein play a critical role in HCA<jats:sub>3<\/jats:sub>\u2010activated ERK1\/2 phosphorylation, whereas \u03b2\u2010arrestins and Src were not required for ERK1\/2 activation.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold>We have described the molecular mechanisms underlying the coupling of human HCA<jats:sub>3<\/jats:sub>receptors to the ERK1\/2 MAP kinase pathway in CHO\u2010K1 and A431 cells, which implicate the G<jats:sub>i<\/jats:sub>protein\u2010initiated, PLC\/PKC\u2010 and platelet\u2010derived growth factor receptor\/EGFR transactivation\u2010dependent pathways. These observations may provide new insights into the pharmacological effects and the physiological functions modulated by the HCA<jats:sub>3<\/jats:sub>\u2010mediated activation of ERK1\/2.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2012.01875.x","type":"journal-article","created":{"date-parts":[[2012,1,31]],"date-time":"2012-01-31T10:10:45Z","timestamp":1328004645000},"page":"1756-1773","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Activated human hydroxy\u2010carboxylic acid receptor\u20103 signals to MAP kinase cascades via the PLC\u2010dependent PKC and MMP\u2010mediated EGFR 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