Regulation of adenylyl cyclase by noradrenaline and tumour necrosis factor in rat cardiomyocytes

Abstract

The regulation of adenylyl cyclase components and of adenylyl cyclase activity by noradrenaline and tumour necrosis factor α (TNFα) was studied in rat cardiomyocytes. Long-term treatment of rat cardiomyocytes in the presence of noradrenaline leads, in addition to a down-regulation of β₁-adrenoceptors, to an increase in the level of inhibitory G protein α-subunits and to a heterologous descnsitization of adenylyl cyclase stimulation. Similar to the noradrenaline exposure, incubation of the cardiomyocytes in the presence of the cytokine TNFα (10 U. ml⁻¹) also increases the level of G_1α proteins. However, in contrast to the noradrenaline treatment, which apparently induces a selective up-regulation of G_1α, the TNFα exposure also increases the level or activity of other components of adenylyl cyclase, such as the level of membrane β₃₆-subunits of G proteins and, most likely, the level of the α-subunits of the stimulatory G protein (G_sα) and the activity of adenylyl cyclase catalytic subunit. While noradrenaline treatment desensitizes receptor-dependent and independent adenylyl cyclase activity, treatment of the cells with TNFα induces a sensia'zation of adenylyl cyclase stimulation. The data indicate that only a selective increase in the level of inhibitory G protein a subunits decreases adenylyl cyclase activity. The hypersensitivity of adenylyl cyclase induced by TNFα exposure may be due to concomitant alterations of other components of the adenylyl cyclase signal transduction system.