3,5,3'-Tri-iodo-L-thyronine acutely regulates a protein kinase C-sensitive, Ca2+-independent, branch of the hepatic α1-adrenoreceptor signalling pathway

This work aimed to investigate the acute effect of the thyroid hormone 3,5,3'-tri-iodo-L-thyronine (T-3) 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 T-3 either in perfused liver or in isolated liver cells. However, T-3 exerted a powerful inhibitory effect on the alpha(1)- adrenoreceptor-mediated responses. The promptness of this T-3 effect rules out that it was the result of rate changes in gene(s) transcription. T-3 inhibited the alpha(1)-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, T-3 enhanced the alpha(1)-agonist-induced increase in cytosolic free Ca2+ and impeded the intracellular alkalinization, Since T-3 also prevented the alpha(1)-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 T-3 to prevent the alpha(1)-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. T-3 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 T-3 actions. The differential effect of T-3 in enhancing the alpha(1)-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 T-3 (less than or equal to 10 nM) in perturbing the alpha(1)-adrenoreceptor-mediated response suggests its physiological significance.