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Inhibition of Thyroid Adenylate Cyclase by Thyroid Hormone: A Possible Locus for the "Short-Loop" Negative Feedback Phenomenon¹

Division of Endocrinology and Metabolism, Department of Medicine, Cook County Hospital Chicago, Illinois 60612

Abstract

The effect of thyroid hormone on bovine thyroid plasma membrane adenylate cyclase activity was studied in order to determine if the locus of the previously observed "short-loop" negative feedback in the thyroid (J Clin Invest 57: 745, 1976) is the adenylate cyclase enzyme system.

Adenylate cyclase activity was measured in bovine thyroid plasma membrane. This preparation was responsive to TSH (100 mU/ml), PGE₂ (5 x 10^–M) and F^– (10^–2M) with increases in activity of 70%, 50%, and 1,000% over basal (1.3 ± 0.5 pmol cAMP formed/10 min/mg protein), respectively. L-Thyroxine (T₄), 3,5,3'-triiodothyronine (T₃), D-thyroxine, 3,5,3'-triiodothyroacetic acid, and 3,3',5'-triiodothyronine inhibited basal adenylate cyclase activity by 25-35% in contrast, only T₄, T₃, and D-T₄ inhibited TSH- and PGE₂-stimulated adenylate cyclase activity. F^– stimulation was unaffected. Lubrol-PX, non-ionic detergent, abolished TSH-induced adenylate cyclase activity, but plasma membrane so treated was still responsive to PGE₂ and F^–. Thyroid hormone inhibited both basal and PGE_2– induced activity in Lubrol-treated membrane by 35% F^–-induced activity was unaffected. Although both GTP (3 x 10^–4M) and ITP (1 x 10^–4M) enhanced basal adenylate cyclase activity in intact plasma membrane, the inhibitory effect of thyroid hormone was still seen. Thyroid hormone did not alter plasma membrane ATP'ase activity.

T₃ (5 µg) was shown to inhibit (by 78–97%) both TSH and dibutyryl cAMP [(Bu)₂cAMP] stimulation of rat thyroid ornithine decarboxylase activity (ODC). Additionally, T₃ pretreatment of the McKenzie bioassay mouse led to a dose-related reduction in both TSH- and (Bu)₂cAMP-stimulated thyroid hormone release. Conclusions: 1) Thyroid hormone directly inhibits thyroid adenylate cyclase activity; this effect is not exerted at the TSH receptor or the catalytic site of the enzyme, but may involve the "coupler" subunit of the enzyme. 2) Thyroid hormone directly inhibits (Bu)₂cAMP stimulation of thyroid function. 3) Thus, circulating thyroid hormones may regulate thyroid function by a "shortloop" feedback mechanism(s) effected prior to as well as following generation of thyroidal cAMP.

Footnotes

Supported by a Grant (AM 17561) from the U.S.P.H.S.

¹ Presented in part to the 58th Annual Meeting of the Endocrine Society, San Francisco, California, June 23–25, 1976.

Abbreviations used in this paper: cAMP, cyclic adenosine 3'-5'monophosphate; (Bu)₂cAMP, N⁶-2'-O-dibutyryl cyclic adenosine 3',5'-monophosphate; PGE₂, prostaglandin E₂; PGF₂, prostaglandin F₂; T₃, 3,5,3'-triiodothyronine; T₄, L-thyroxine; rT₃, 3,3',5'-triiodothyronine.

Received September 2, 1976.