Modulation of Adenylate Cyclase/Cyclic AMP Response by Thyrotropin and Prostaglandin E 2 in Cultured Thyroid Cells

Two different independent processes are operating in cultured thyroid cells to regulate adenylate cyclase/cyclic AMP responsiveness to thyroid stimulators (thyrotropin and prostaglandin E 2 ): firstly, refractoriness or negative regulation [preceding paper], which is specific for each thyroid stimulator, is not mediated by cyclic AMP and is not accompanied by alteration of adenylate cyclase activity; secondly, positive regulation which is characterized by an augmentation of the cyclic AMP response stimulated by thyrotropin and prostaglandin E 2 . This process is not specific for each thyroid stimulator and is a state of increased susceptibility of cyclic AMP synthesis to stimulation, accompanied by increased activity of the catalytic subunit of adenylate cyclase. Positive regulation is apparently mediated by increased intracellular cyclic AMP levels. It is a time‐dependent and dose‐dependent process. Very low concentrations (5–50 μU/ml) of thyrotropin augmented cyclic AMP synthesis stimulated by thyrotropin and prostaglandin E 2 whereas higher concentrations (above 0.1 mU/ml) augmented prostaglandin E 2 stimulation but induced refractoriness to thyrotropin. Prostaglandin E 2 (0.1 to 10 μM) augmented thyrotropin stimulation and dibutyryl adenosine 3′:5′‐monophosphate (0.3 to 2 mM) augmented thyrotropin and prostaglandin E 2 stimulation. Positive regulation is a slow process which develops within days and increases up to day 5 in culture. Experiments using inhibitors suggested that protein synthesis is required for the full expression of the increase in adenylate cyclase activity induced by the studied thyroid stimulators.