3,5,3′-Tri-iodo-l-thyronine acutely regulates a protein kinase C-sensitive, Ca2+-independent, branch of the hepatic α1-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.

Membrane-Initiated Steroid Actions and the Proteins that Mediate Them

“…Ion fluxes are common consequences of the rapid workings of steroidal compounds. The channel opening most commonly affected (or more frequently measured) is Ca++ (24,26,52,55,57,59,60,(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95). These examples include the actions of glucocorticoids (95), progestins (24,26,(76)(77)(78)(79)(80), vitamin D (52, 81, 91), thyroid hormone (94), androgens (81,82,90), mineralocorticoids (55), and estrogens (59,60,(83)(84)(85)(86)(87)(88)(89)93).…”

“…Kinases are also frequently controlled by their own phosphorylation status. Examples of rapid steroid-induced changes in kinase activities include many different categories of protein kinases including both tyrosine and serinekhreonine kinases (29, 12 l), cyclic nucleotide-, Ca++-, inositol phosphate-, or DAG-dependent kinases (24,35,41,54,76,94,101,113,118,(122)(123)(124), and kinases associated with cell proliferation such as MAP kinase (19,30,123,(125)(126)(127)(128) and other ERKs (19,29,30,62,128,129). One wonders if further analysis will also reveal participation of phosphatase activities in these schemes, although no examples of this part of the general mechanism have yet appeared.…”

Short-term effects of thyroid hormones on Na+-K+-ATPase activity of chick embryo hepatocytes during development: focus on signal transduction

“…Together, these results provide evidence for the involvement of plasma membrane receptors and plasma membrane-associated signal transduction pathways in the short-term nongenomic effects of thyroid hormones. The short-term effects of thyroid hormones were in many cases found to involve signal transduction pathways and second messenger systems that lead to activation of protein kinases (5,20,28,35,36,41,46,47,62). It was recently shown that in CV-1 cells, rapid effects elicited by T 4 were initiated at the plasma membrane level through the interaction with an ␣ V ␤ 3 integrin (5).…”