ALPHA(1)-ADRENERGIC STIMULATION INHIBITS 3,5,3'-TRIIODOTHYRONINE-INDUCED EXPRESSION OF THE RAT-HEART SARCOPLASMIC-RETICULUM CA2-TRIPHOSPHATASE GENE( ADENOSINE)

The interactions between the beta-adrenergic system and thyroid hormon e (T-3) on cardiac function have been investigated in detail. In addit ion to beta-adrenoreceptors, alpha(1)-adrenergic receptors are present in the mammalian heart. The interactions T-3 and the alpha(1)-adrener gic system remain, however, poorly understood. T-3 stimulates the expr ession and transcription of the sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2) gene, a protein vital in the control of cardia c calcium transients and contractility. We show that in rat cardiac my ocytes, the stimulatory effect of T-3 on SERCA2 messenger RNA expressi on and gene transcription is inhibited by an alpha(1)-adrenergic agoni st. We demonstrate that direct activation of the alpha(1)-adrenergic s ignaling pathway, using mutant constitutively active G protein (G(4)) similarly down-regulated the T-3 effect on SERCA2 transcription. The c ombined effect of the thyroid hormone receptor and retinoid X receptor s on T-3-stimulated SERCA2 gene transcription was also markedly attenu ated by alpha(1)-adrenergic stimulation. These results suggested that activation of the alpha(1)-adrenergic signaling pathway has an inhibit ory effect on T-3-dependent SERCA2 gene transcription. As this inhibit ory effect of alpha(1)-adrenergic stimulation occurs when only one thy roid hormone response element (TRE) drives reporter expression, it is most likely mediated by an alteration of the nuclear factors binding t o the TRE or by influencing the interaction of the nuclear factors bin ding to the TRE or by influencing the interaction of the TRE complex w ith the basal transcriptional machinery.