3,5,3'-Tri-iodo-L-thyronine acutely regulates a protein kinase C-sensitive, Ca2+-independent, branch of the hepatic alpha1-adrenoreceptor signalling pathway.

This work aimed to investigate the acute effect of the thyroid hormone 3,5,3'-tri-iodo-L-thyronine (T3) in regulating the hepatic metabolism either directly or by controlling the responsiveness to Ca2+-mobilizing agonists. We did not detect any acute metabolic effect of T3 either in perfused liver or in isolated liver cells. However, T3 exerted a powerful inhibitory effect on the alpha1-adrenoreceptor-mediated responses. The promptness of this T3 effect rules out that it was the result of rate changes in gene(s) transcription. T3 inhibited the alpha1-adrenoreceptor-mediated sustained stimulation of respiration and release of Ca2+ and H+, but not the glycogenolytic or gluconeogenic responses, in perfused liver. In isolated liver cells, T3 enhanced the alpha1-agonist-induced increase in cytosolic free Ca2+ and impeded the intracellular alkalinization. Since T3 also prevented the alpha1-adrenoreceptor-mediated activation of protein kinase C, its effects on pH seem to be the result of a lack of activation of the Na+/H+ exchanger. The failure of T3 to prevent the alpha1-adrenergic stimulation of gluconeogenesis despite the inhibition of protein kinase C activation indicates that the elevation of cytosolic free Ca2+ is a sufficient signal to elicit that response. T3 also impaired some of the angiotensin-II-mediated responses, but did not alter the effects of PMA on hepatic metabolism, indicating, therefore, that some postreceptor event is the target for T3 actions. The differential effect of T3 in enhancing the alpha1-adrenoreceptor-mediated increase in cytosolic free Ca2+ and preventing the activation of protein kinase C, provides a unique tool for further investigating the role of each branch of the signalling pathway in controlling the hepatic functions. Moreover, the low effective concentrations of T3 (<= 10 nM) in perturbing the alpha1-adrenoreceptor-mediated response suggests its physiological significance.