title: Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac beta-adrenergic receptor responsiveness.
abstract: Although thyroid hormones are known to modulate cardiac beta-adrenergic receptor expression, the physiologic implications of these changes in the cardiac manifestations of altered thyroid hormone metabolism have been disputed. This study examined whether thyroid hormone modulates signaling via the cyclic adenosine monophosphate (cAMP) pathway by regulating cardiac adenylyl cyclase (AC) isoform expression. Northern blot analyses and AC enzyme assays were performed on preparations from hypothyroid, euthyroid, and hyperthyroid 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 isoforms 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 euthyroid ventricles, but catalytic AC activation by forskolin and Mn was significantly reduced by 35% in membranes obtained from hyperthyroid ventricles. AC activation through beta-adrenergic receptor stimulation by isoproterenol was not altered by thyroid hormone status. Thus, the effect of thyroid hormone to repress AC catalytic activity would be anticipated to offset the increase in beta-adrenergic receptor expression in hyperthyroidism. These studies identify cardiac AC enzymes as important targets for thyroid hormone-dependent regulation of signaling via the cAMP pathway, and support the finding that cardiac adrenergic responsiveness is unaltered in thyroid disease states.
authors.affiliation: Department of Medicine, North Shore University Hospital/New York University School of Medicine, Manhasset 11030, USA.
authors.forename: K
authors.initials: K
authors.lastname: Ojamaa
authors.forename: I
authors.initials: I
authors.lastname: Klein
authors.forename: A
authors.initials: A
authors.lastname: Sabet
authors.forename: S F
authors.initials: SF
authors.lastname: Steinberg
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D005576:Colforsin / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006980:Hyperthyroidism / Q000201:enzymology / Q000378:metabolism; D007037:Hypothyroidism / Q000201:enzymology / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D013963:Thyroid Hormones / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D007527:Isoenzymes; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D013963:Thyroid Hormones; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D000262:Adenylyl Cyclases; D007545:Isoproterenol