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

ABSTRACT: 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.

SUBMITTER: Daza FJ

PROVIDER: S-EPMC1219324 | biostudies-other | 1998 Apr

REPOSITORIES: biostudies-other

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Project description:We investigated 3,3',5-tri-iodo-l-thyronine transport by human erythrocytes and by ;ghosts' prepared from these cells. Uptake of tri-iodothyronine by erythrocytes at 37 degrees C was time-dependent with a maximum reached after 60min. Tracer analysis after incubation for 1min revealed only one saturable binding site, with K(m) 128+/-19nm (mean+/-s.e.m.; n=7) and V(max.) 4.6+/-0.7pmol of tri-iodothyronine/min per 6x10(7) cells. After 10min incubation K(m) 100+/-16nm (n=10) was found with V(max.) 7.7+/-1.2pmol of tri-iodothyronine/10min per 6x10(7) cells. At 0 degrees C the uptake system is still active, with K(m) 132+/-26nm and V(max.) 1.8+/-0.3pmol of tri-iodothyronine/10min per 6x10(7) cells. The V(max.) with intact cells is 5-fold greater than the V(max.) with membranes derived from the same amount of cells when uptake studies are performed in media with similar free tri-iodothyronine concentrations. This indicates that at least 80% of tri-iodothyronine taken up by the intact erythrocytes enters the cell. This saturable uptake system can be inhibited by X-ray-contrast agents in a dose-dependent fashion. (+/-)-Propranolol, but not atenolol, has the same effect, indicating that the membrane-stabilizing properties of (+/-)-propranolol are involved. Furthermore, there is no inhibition by ouabain or vanadate, which indicates that tri-iodothyronine uptake is not dependent on the activity of Na(+)+K(+)-dependent adenosine triphosphatase. We have prepared erythrocyte ;ghosts', resealed after 2.5min with 0mm-, 2mm- or 4mm-ATP inside. Inclusion of ATP and integrity of the membrane of the erythrocyte ;ghosts' were verified on the basis of an ATP-concentration-dependent functioning of the Ca(2+) pump. No difference was found in the uptake of tri-iodothyronine by erythrocyte ;ghosts' with or without ATP included, indicating that uptake of tri-iodothyronine is not ATP-dependent. The following conclusions are drawn. (1) Tri-iodothyronine enters human erythrocytes. (2) There is only one saturable uptake system present for tri-iodothyronine, which is neither energy (i.e. ATP)-dependent nor influenced by the absence of an Na(+) gradient across the plasma membrane. This mode of uptake of tri-iodothyronine by human erythrocytes is in sharp contrast with that of rat hepatocytes, which uptake system is energy-dependent and ouabain-sensitive [Krenning, Docter, Bernard, Visser & Hennemann (1978) FEBS Lett.91, 113-116; Krenning, Docter, Bernard, Visser & Hennemann (1980) FEBS Lett.119, 279-282]. (3) X-ray-contrast agents inhibit tri-iodothyronine uptake by erythrocytes in a similar fashion to that by which they inhibit the uptake of tri-iodothyronine by rat hepatocytes [Krenning, Docter, Bernard, Visser & Hennemann (1982) FEBS Lett.140, 229-233].

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

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