Editorial [Hot Topic:The Extranuclear Life of the Nuclear Receptor Hormone Family: New Therapeutic Possibilities (Guest Editor: Sandra Incerpi)]

This Theme Issue is dedicated to the emerging field of nongenomic or extranuclear effects of the nuclear receptor hormone family. It is nowadays recognized that most hormones working through nuclear receptors have a wider pleiotropic action than the one elicited by the interaction within the nucleus. For these hormones also extranuclear effects have been reported, with a rapid time course that cannot be explained by a genomic mechanism. Much of the pioneering work was done by of Paul J. Davis and his group, and it is appropriate that their contribution on the state of the art of nongenomic effects of thyroid hormones open this issue. They have recently identified the long-searched plasma membrane receptor for thyroxine as the αVβ3 integrin; the hormone binds at the Arg-Gly-Asp recognition site as shown by the capability of RGD peptides to inhibit thyroid hormone action at the cell surface. This finding explains several, if not all, of the extranuclear effects of this class of hormones, and opens a new scenario for the years to come. Membrane transport systems account for the largest group of nongenomic effects of thyroid hormones and the review by Farias et al. covers this topic with a wide survey of this important field. Thyroid hormones cause weight reduction by metabolic rate and cholesterol reduction through enhanced expression of LDL receptors and cholesterol metabolism, but the administration of thyroid hormones also gives rise to side effects that may induce thyreotoxicosis with particularly important effects on the cardiovascular system (tachycardia and atrial fibrillation). Pharmacological research has been aimed at the development of thyroid hormone analogs to be used in case of obesity that produce the positive effects on lipid metabolism without the deleterious effects on the heart. The contribution by Goglia's group focuses on the effects of diiodothyronines on mitochondria, and on the novel finding that 3,5-diiodothyronine appears to be devoid of the side effects causing thyreotoxicosis. The last contribution on thyroid hormones comes from Zhao et al. and deals with the complicated interaction between estrogens and thyroid hormones, that appears to be particularly relevant for neuroendocrine feedback and reproductive behavior. In analogy to estrogens, thyroid hormones exhibit a large range of actions, in particular they are critical for growth, development and differentiation. Neonatal hypothyroidism results in cretinism, a disorder characterized by mental retardation and skeletal defects. Hormone therapy during pregnancy or to the child immediately after birth, may reverse a situation that otherwise will become irreversible, resulting in a more or less serious cognitive deficiency. A plasma membrane receptor for estrogens has not been identified yet and contradictory results are reported in the literature, suggesting either that the membrane receptor is identical or very similar to a nuclear receptor (ERα or ERβ) or that it is a totally different protein. Nongenomic effects of estrogens have been found in many different tissues, and the paper by Zhao et al. reports on these controversial findings. It is possible that many actions of estrogens at the membrane of the neuroendocrine system are mediated through modulation of nongenomic responses such as the effects on voltage-operated calcium channels and intracellular calcium stores. Another contribution on estrogens, and a step forward in the understanding of both the mechanisms and roles of their extranuclear effects, is given by Marino and Ascenzi. They recently showed that ERα can undergo Spalmitoylation, a modification that represents a major determinant for ERα at the plasma membrane and is important for the modulation of nongenomic effects of estrogens. Palmitoylation enables the plasma membrane exposure of ERα and promotes downstream signaling for estradiol-mediated proliferation and survival of cancer cells, offering a new target for anti-tumor therapy. Glucocorticoid receptors have been studied for many years and the multi-billion-dollar market for this class of compounds is growing rapidly as side effect profiles are reduced and newly developed molecules travels from the laboratories to the pill boxes. The contribution from Daufeldt and Allera deals with the physiological and clinical significance of the interaction of natural and synthetic glucocorticoids with plasma-membrane-residing glucocorticoid receptors. Glucocorticoids have powerful anti-inflammatory and immunomodulatory effects as well as apoptotic competence in many lymphoid malignancies, and various glucocorticoids have been essential therapeutic tools for the past 50 years despite the significant risks associated with their long-term application, e.g. rapid bone loss, clinical osteoporosis, joint necrosis, metabolic effects or Cushing syndrome......