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In this study, we report on the activation of MAPK by muscarinic acetylcholine receptors in astroglial cells, namely the 1321N1 human astrocytoma cell line, primary rat cortical astrocytes, and fetal human astrocytes. Carbachol caused a rapid and transient phorphorylation of MAPK (ERK1\/2) in all cell types, with an increase in MAPK activity, without changing the levels of MAPK proteins. Human astrocytoma cells were used to characterize the effect of carbachol on MAPK. Experiments with M<jats:sub>2<\/jats:sub>\u2010 and M<jats:sub>3<\/jats:sub>\u2010receptor subtype\u2010selective antagonists, and with pertussis toxin, indicated that the M<jats:sub>3<\/jats:sub> subtype is responsible for activating MAPK in glial cells. Pretreatment of cells with the protein kinase C (PKC) inhibitor bisindolylmaleimide I, or downregulation of PKC by 24\u2010h treatment with the phorbol ester TPA inhibited carbachol\u2010induced MAPK activation. Additional experiments with PKC \u03b1\u2010 or PKC \u03f5\u2010specific compounds indicated that the \u03f5 isozyme of PKC is primarily involved in MAPK activation by carbachol. Chelation of calcium also inhibited MAPK activation by carbachol. Two MEK (MAPK kinase) inhibitors inhibited carbachol\u2010induced DNA synthesis but only at concentrations that exceeded those sufficient to block carbachol\u2010induced MAPK activation. Ethanol (\u2264200 mM) had no effect on MAPK when present alone and did not affect carbachol\u2010induced MAPK activation under various experimental conditions, although it inhibits carbachol\u2010induced DNA synthesis at low concentrations (10\u2013100 mM). These results suggest that activation of MAPK by carbachol may be necessary but not sufficient for its mitogenic effect in astroglial cells, and that does not represent a target for ethanol\u2010induced inhibition of DNA synthesis elicited by muscarinic receptors. GLIA 35:111\u2013120, 2001. \u00a9 2001 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.1076","type":"journal-article","created":{"date-parts":[[2002,9,10]],"date-time":"2002-09-10T23:28:20Z","timestamp":1031700500000},"page":"111-120","source":"Crossref","is-referenced-by-count":51,"title":["Activation of mitogen\u2010activated protein kinase by muscarinic receptors in astroglial cells: Role in DNA synthesis and effect of 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