Regulation of adenylyl cyclase by noradrenaline and tumour necrosis factor alpha in rat cardiomyocytes.
The regulation of adenylyl cyclase components and of adenylyl cyclase activity by noradrenaline and tumour necrosis factor alpha (TNF alpha) was studied in rat cardiomyocytes. Long-term treatment of rat cardiomyocytes in the presence of noradrenaline leads, in addition to a down-regulation of beta 1-adrenoceptors, to an increase in the level of inhibitory G protein alpha-subunits and to a heterologous desensitization of adenylyl cyclase stimulation. Similar to the noradrenaline exposure, incubation of the cardiomyocytes in the presence of the cytokine TNF alpha (10 U.ml-1) also increases the level of Gi alpha proteins. However, in contrast to the noradrenaline treatment, which apparently induces a selective up-regulation of Gi alpha, the TNF alpha exposure also increases the level or activity of other components of adenylyl cyclase, such as the level of membrane beta 36-subunits of G proteins and, most likely, the level of the alpha-subunits of the stimulatory G protein (Gs alpha) and the activity of adenylyl cyclase catalytic subunit. While noradrenaline treatment desensitizes receptor-dependent and independent adenylyl cyclase activity, treatment of the cells with TNF alpha induces a sensitization of adenylyl cyclase stimulation. The data indicate that only a selective increase in the level of inhibitory G protein alpha subunits decreases adenylyl cyclase activity. The hypersensitivity of adenylyl cyclase induced by TNF alpha exposure may be due to concomitant alterations of other components of the adenylyl cyclase signal transduction system.
Reithmann
C
C
Medizinische Klinik I, Universität München, Klinikum Grosshadern, Germany.
Gierschik
P
P
Jakobs
K H
KH
Werdan
K
K
D000262:Adenylyl Cyclases / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D011943:Receptors, Adrenergic, beta; D014409:Tumor Necrosis Factor-alpha; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D009638:Norepinephrine