Background ��� In cardiac myocytes, stimulation of 慣1-adrenoceptor (慣1-AR) leads to a hypertrophic phenotype. The Gh protein (Transglutaminase II, TGII) is tissue type transglutaminase and transmits the 慣1B-AR signal with GTPase activity. Little is known about Gh-mediated intracellular signal transductions to develop the hypertrophy. The aim of this study was to elucidate how Gh mediates norepinephrine-stimulated intracellular signal transductions leading to the hypertrophic responses in RGS4-transfected neonatal rat cardiomyocytes. Methods and Results ��� To elucidate the molecular mechanisms of a 慣1-adrenoceptor/Gh-mediated hypertrophic responses, we examined the effects of norephinephrine on the activation of MAP kinases and their up-stream regulators, protein kinase C, Ras, and MEK1,2 and protooncogens expression, and on the protein synthesis in RGS4-transfected neonatal rat cardiomyocytes. Norepinephrine- induced ERKs activation was inhibited by an 慣1-AR blocker (prazosin), but not by an 棺-AR blocker (propranolol). Overexpression of the Gh protein stimulated norepinephrine-induced ERKs activation, which was inhibited by 慣1-AR blocker (prazosin). Co-overexpression of Gh and RSG4, the regulatory protein of Gq, leaded to the partial decrease of norepinephrine-induced hypertrophic responses and activated PKC/MEK1,2/ ERKs, leading up-regulation of c-myc. Conclusions ��� Norepinephrine induces hypertrophy in neonatal rat cardiomyocytes through 慣1-AR stimulation and Gh is partly involved in norepinephrine-induced PKC/MEK1,2/ERKs activation. Activation of Gh-mediated PKC/MEK1,2/ ERKs lead to up-regulation of c-myc.