Extranuclear effects of thyroid hormones and analogs during development: An old mechanism with emerging roles

Abstract

Thyroid hormones, T3 (triiodothyronine) and T4 (thyroxine), induce a variety of long-term effects on important physiological functions, ranging from development and growth to metabolism regulation, by interacting with specific nuclear or cytosolic receptors. Extranuclear or nongenomic effects of thyroid hormones are mediated by plasma membrane or cytoplasmic receptors, mainly by αvβ3 integrin, and are independent of protein synthesis. A wide variety of nongenomic effects have now been recognized to be elicited through the binding of thyroid hormones to this receptor, which is mainly involved in angiogenesis, as well as in cell cancer proliferation. Several signal transduction pathways are modulated by thyroid hormone binding to αvβ3 integrin: protein kinase C, protein kinase A, Src, or mitogen-activated kinases. Thyroid hormone-activated nongenomic effects are also involved in the regulation of Na+-dependent transport systems, such as glucose uptake, Na+/K+-ATPase, Na+/H+ exchanger, and amino acid transport System A. Of note, the modulation of these transport systems is cell-type and developmental stage-dependent. In particular, dysregulation of Na+/K+-ATPase activity is involved in several pathological situations, from viral infection to cancer. Therefore, this transport system represents a promising pharmacological tool in these pathologies.

Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain

“…In addition, the elevated expression of OATP1C1 in the pyramidal cells could be controlling in normal conditions the availability of the extracellular T4, and subsequently, its non-genomic actions by binding to plasma membrane receptors. The main non-genomic actions described for T4 relate to the modulation of different intracellular signaling pathways, as well as Na + -dependent transport systems, at the level of the plasma membrane integrin αvβ3 receptors [ 95 , 96 ]. Additionally, in OATP1C1-expressing neurons, the extracellular T4 could be uptaken by OATP1C1 to facilitate T4 deiodination to reverse T3 (rT3) by the action of DIO3, a deiodinase that is mainly expressed in neurons in the adult brain [ 97 ], although during CNS development and under pathophysiological conditions it can also be expressed in different cerebral regions and neural cells [ 98 ].…”

Modulation of Integrin αvβ3 Activation and Signaling in BV-2 Microglial Cells and THP-1 Monocytes by Thyroid Hormones

“…The inhibition is due to cAMP. We suggest that the ionic environment caused by the inhibition of the Na + -pump may represent an immunologically privileged environment for the embryo able, in that way, to survive to a difficult situation such as hatching [2,[136][137][138].…”

“…Thyroid hormones (THs) in mammals are essential for normal development, growth, metabolic regulation, neural differentiation and also play an important role in the maintenance of adult brain function [1][2][3][4][5]. Recently, it has been proposed that changes in each of these hormones may be relevant to the vasculopathic complications of COVID-19 infection [6].…”

Nucleotide Contribution to the Functioning of SERT, Na<sup> </sup>/K<sup> </sup> ATPase and GPCR Proteins

“…An inverse relationship between thyroxine activation of adenyl cyclase and N/K ATPase activity is observed in cat heart homogenates and rat synaptosomal membranes [36]. Protein kinase phosphorylation of the catalytic alpha unit, containing ATP and ouabain binding sites, modulates ATPase pump activity [37]. The release of the neurotransmitters norepinephrine and 5-HT and their effects on N/K ATPase activity may be subject to reciprocal control [14] [38].…”