{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T15:47:51Z","timestamp":1777909671338,"version":"3.51.4"},"reference-count":38,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2011,10,19]],"date-time":"2011-10-19T00:00:00Z","timestamp":1318982400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Ocular Pharmacology and Therapeutics"],"published-print":{"date-parts":[[2012,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose:<\/jats:title>\n                    <jats:p>\u03b2-Adrenergic receptor (\u03b2AR) agonists reduce intraocular pressure (IOP) by increasing aqueous outflow through the trabecular meshwork (TM). However, although this effect is well established, the specific signaling mechanisms responsible are less clear. To address this, the current study examined \u03b2AR signaling in primary human trabecular meshwork cells (HTMCs), specifically, focusing on the effect of \u03b2AR activation on the extracellular signal regulated kinases 1\/2 (ERK).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>HTMCs were cultured and assessed for \u03b2AR expression by both immunofluorescence and reverse-transcription\u2013polymerase chain reaction. The effect of \u03b2AR activation on ERK phosphorylation was examined in these cells by In-Cell Western\u2122 analysis. Pharmacological approaches were used to characterize the mechanism of the \u03b2AR effect on ERK.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Treatment of HTMCs with the nonselective \u03b2AR agonist, isoproterenol (ISO), decreased the basal phospho-ERK (pERK) level, through actions at the \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR. The response was insensitive to pertussis toxin (PTx), but pretreatment with cholera toxin (CTx) resulted in a reversal of the response, such that ISO treatment instead increased pERK, thus implicating G\u03b1\n                      <jats:sub>s<\/jats:sub>\n                      in the inhibitory pERK response. The adenylyl cyclase activator, forskolin, also decreased pERK, suggesting the involvement of adenylyl cyclase and cAMP, whereas a protein kinase A (PKA) inhibitor, H-89, blocked both ISO and forskolin-mediated pERK inhibition in HTMCs. Finally, a closer examination of the pERK increase generated in the presence of CTx demonstrated that it was also insensitive to PTx, and appeared to have differing rank orders of efficacy for various \u03b2AR agonists compared with the inhibitory pERK pathway in HTMCs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      A novel \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR-signaling pathway leading to a decrease in pERK, which was dependent on G\u03b1\n                      <jats:sub>s<\/jats:sub>\n                      , cAMP, and PKA, was identified in HTMCs. A competing \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR signaling pathway resulting in increased pERK was also identified. Since \u03b2AR effects on aqueous humor (AH) outflow have been linked to cAMP, and inhibition of ERK in TM cells has recently been suggested as increasing AH outflow, our findings suggest that the inhibitory \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR-pERK pathway likely represents the mechanism by which \u03b2AR agonists decrease IOP. The presence of a competing \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR-ERK activation pathway in the same cells suggests that this is an ideal system for the development and validation of functionally selective \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      AR agonists.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/jop.2011.0016","type":"journal-article","created":{"date-parts":[[2011,10,19]],"date-time":"2011-10-19T09:39:09Z","timestamp":1319017149000},"page":"17-25","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Identification of Novel Competing \u03b2\n                    <sub>2<\/sub>\n                    AR Phospho-Extracellular Signal Regulated Kinase 1\/2 Signaling Pathways in Human Trabecular Meshwork Cells"],"prefix":"10.1177","volume":"28","author":[{"given":"Brian D.","family":"Hudson","sequence":"first","affiliation":[{"name":"Dalhousie University","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie E.M.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Dalhousie University","place":["Canada"]},{"name":"Dalhousie University","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2011,10,19]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2165\/00002512-200522010-00001"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2003.09.021"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.ijg.0000169397.32674.5e"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.8.18.3237"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.2165\/00002512-200825090-00002"},{"key":"e_1_3_3_7_2","first-page":"2672","article-title":"Epinephrine increases facility of outflow and cyclic AMP content in the human eye in vitro","volume":"33","author":"Erickson-Lamy K.A.","year":"1992","unstructured":"Erickson-Lamy K.A., , Nathanson J.A. 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