Calreticulin inhibits the MEK1,2-ERK1,2 pathway in α₁-adrenergic receptor/G_h-stimulated hypertrophy of neonatal rat cardiomyocytes

In cardiac myocytes, stimulation of α₁-adrenoceptor (AR) leads to a hypertrophic phenotype. The G_h protein (transglutaminase II, TGII) is tissue type transglutaminase and transmits the α_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 α₁-adrenoceptor/G_h signaling. In neonatal rat cardiomyocytes, norepinephrine-induced ERKs activation was inhibited by an α₁-adrenoceptor blocker (prazosin), but not by an β-adrenoceptor blocker (propranolol). Overexpression of the G_h protein stimulated norepinephrine-induced ERKs activation, which was inhibited by α-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 α₁-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.