Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac beta-adrenergic receptor responsiveness

Although thyroid hormones are known to modulate cardiac beta-adrenergic rec eptor expression, the physiologic implications of these changes in the card iac manifestations of altered thyroid hormone metabolism have been disputed . This study examined whether thyroid hormone modulates signaling via the c yclic adenosine monophosphate (cAMP) pathway by regulating cardiac adenylyl cyclase (AC) isoform expression. Northern blot analyses and AC enzyme assa ys were performed on preparations from hypothyroid, euthyroid, and hyperthy roid rat ventricles. Steady-state levels of cardiac AC mRNA types V and VI in hypothyroid ventricles were 173% +/- 8% and 149% +/- 12%, respectively, of the values in euthyroid ventricles (P < .01). This increase in AC mRNA i soforms was accompanied by a 1.5-fold increase (P < .05) in the activation of catalytic AC by forskolin and Mn. In contrast, the relative abundance of transcripts for types V and VI AC was similar in hyperthyroid and euthyroi d ventricles, but catalytic AC activation by forskolin and Mn was significa ntly reduced by 35% in membranes obtained from hyperthyroid ventricles. AC activation through beta-adrenergic receptor stimulation by isoproterenol wa s not altered by thyroid hormone status. Thus, the effect of thyroid hormon e to repress AC catalytic activity would be anticipated to offset the incre ase in beta-adrenergic receptor expression in hyperthyroidism. These studie s identify cardiac AC enzymes as important targets for thyroid hormone-depe ndent regulation of signaling via the cAMP pathway, and support the finding that cardiac adrenergic responsiveness is unaltered in thyroid disease sta tes. Copyright (C) 2000 by W.B, Saunders Company.