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

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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 is the adenylate cyclase enzyme system. Adenylate cyclase activity was measured in bovine thyroid plasma membrane. This preparation was responsive to TSH [thyrotropin] (100 mU[milliunits]/ml), PG[prostaglandin]E2 (5 .times. 10-4 M) and F- (10-2 M) with increases in activity of 70%, 50% and 1000% over basal (1.3 .+-. 0.5 pmol c[cyclic]AMP formed/10 min per 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, a 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 PGE2-induced activity in Lubrol-treated membrane by 35%; F--induced activity was unaffected. Although both GTP (3 .times. 10-4 M) 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 ATPase activity. T3 (5 .mu.g) was shown to inhibit (by 78-97%) both TSH and dibutyryl cAMP [(Bu)2cAMP] stimulation of rat thyroid omithine 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. 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. Thyroid hormone directly inhibits (Bu)2cAMP stimulation of thyroid function. Circulating thyroid hormones may regulate thyroid function by a short-loop feedback mechanism(s) effected prior to as well as following generation of thyroidal cAMP.