title: Calreticulin inhibits the MEK1,2-ERK1,2 pathway in alpha 1-adrenergic receptor/Gh-stimulated hypertrophy of neonatal rat cardiomyocytes.
abstract: In cardiac myocytes, stimulation of alpha(1)-adrenoceptor (AR) leads to a hypertrophic phenotype. The G(h) protein (transglutaminase II, TGII) is tissue type transglutaminase and transmits the alpha(1B)-adrenoceptor signal with GTPase activity. Recently, it has been shown that the calreticulin (CRT) down-regulates both GTP binding and transglutaminase activities of TGII. To elucidate whether G(h) mediates norepinephrine-stimulated intracellular signal transductions leading to activation of extracellular signal-regulated kinases (ERKs) and neonatal rat cardiomyocyte hypertrophy, we examined the effects of G(h) on the activation of ERKs and inhibitory effects of CRT on alpha(1)-adrenoceptor/G(h) signaling. In neonatal rat cardiomyocytes, norepinephrine-induced ERKs activation was inhibited by an alpha(1)-adrenoceptor blocker (prazosin), but not by an beta-adrenoceptor blocker (propranolol). Overexpression of the G(h) protein stimulated norepinephrine-induced ERKs activation, which was inhibited by alpha-adrenoceptor blocker (prazosin). Co-overexpression of G(h) and CRT abolished norepinephrine-induced ERKs activation. Taken together, norepinephrine induces hypertrophy in neonatal rat cardiomyocytes through alpha(1)-AR stimulation and G(h) is partly involved in norepinephrine-induced MEK1,2/ERKs activation. Activation of G(h)-mediated MEK1,2/ERKs was completely inhibited by CRT.
authors.affiliation: Cardiovascular Research Institute and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Yonsei, Seoul 120-752, South Korea.
authors.forename: Kyung-Hye
authors.initials: KH
authors.lastname: Lee
authors.forename: Namho
authors.initials: N
authors.lastname: Lee
authors.forename: Soyeon
authors.initials: S
authors.lastname: Lim
authors.forename: Heekyung
authors.initials: H
authors.lastname: Jung
authors.forename: Young-Guk
authors.initials: YG
authors.lastname: Ko
authors.forename: Hyun-Young
authors.initials: HY
authors.lastname: Park
authors.forename: Yangsoo
authors.initials: Y
authors.lastname: Jang
authors.forename: Hakbae
authors.initials: H
authors.lastname: Lee
authors.forename: Ki-Chul
authors.initials: KC
authors.lastname: Hwang
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D037282:Calreticulin / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D004789:Enzyme Activation; D015151:Immunoblotting; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology; D009638:Norepinephrine / Q000494:pharmacology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D000316:Adrenergic alpha-Agonists; D037282:Calreticulin; D018340:Receptors, Adrenergic, alpha-1; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020929:Mitogen-Activated Protein Kinase Kinases; D009638:Norepinephrine