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The Role of Thyroid Hormone in the Regulation of Hepatic Carbamyl Phosphate Synthetase Activity in Rana catesbeiana^*

VALERIE ANNE GALTON, CHRISTINE M. MORGANELLI, MARK J. SCHNEIDER and KAREN YEE

Department of Physiology, Dartmouth Medical School Hanover, New Hampshire 03756

Abstract

Both spontaneous and thyroid hormone (TH)- induced metamorphosis of Rana catesbeiana are accompanied by a marked increase in the activity of the urea cycle enzyme carbamyl phosphate synthetase (CPS). The increase induced by exogenous TH is de novo synthesis of enzyme and appears to be secondary to an increase in the CPS mRNA level resulting from the elevated plasma TH. Since endogenous TH levels rise sharply during spontaneous metamorphosis, a similar sequence of events would be anticipated. However, after midclimax, CPS activity continues to increase, while plasma TH levels steadily decline, suggesting that other factors are involved. To obtain insight into this problem, the changes in CPS mRNA level during spontaneous development were determined using a mammalian CPS cDNA probe and correlated with changes in CPS activity and plasma T₃ concentration. CPS mRNA level and CPS activity were barely detectable until midprometamorphosis, but both increased rapidly during the latter half of this phase. CPS activity continued to rise, reaching a maximum in the adult frog. The CPS mRNA level, however, was highest during the first half of climax, but declined after midclimax and was relatively low in the adult frog. Studies were also performed in which the rise and fall in the plasma T₃ concentration typical of metamorphic climax were induced by exposure of premetamorphic tadpoles to T₃, followed by its withdrawal. Both CPS activity and CPS mRNA level were induced by T₃, but when plasma T₃ levels fell after removal of the exogenous T₃, CPS mRNA level, but not CPS activity, also decreased. Additional studies indicated that the TH-induced increase in CPS mRNA was evident within 24 h, could be prevented by simultaneous injection of actinomycin-D, and could not be induced in tadpoles undergoing climax; in this phase the T₃ receptors are fully occupied with endogenous TH. When premetamorphic tadpoles were immersed in T₃-containing water (0–500 nM) for 6 days, CPS mRNA, CPS activity, and plasma T₃ concentration increased in parallel, reaching a maximum at 50 nM. At 50 nM T₃, the plasma T₃ level was sufficient to saturate the receptors, and no additional increase in CPS mRNA level or CPS activity was obtained at higher concentrations of T₃. These studies indicate that the CPS mRNA level during spontaneous development correlates with the plasma T₃ concentration and suggest that it is a function of T₃ receptor occupancy. The data are also consistent with an effect of TH on transcription of the CPS gene and with a relatively long half-life of its protein product, the CPS enzyme. (Endocrinology129: 2298–2304,1991)

Footnotes

^* This work was supported by USPHS Grant HD-0902C and was presented in part at the 64th Annual Meeting of the American Thyroid Association, September 1989.

To whom all correspondence and requests for reprints should be addressed.

Supported by USPHS Training Grant AM-07508.

Received April 15, 1991.

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