Preface [ Infectious Disorders Drug Targets - An Arsenal of Knowledge on Pathogen Targets ]

Most of the actions of estrogens are mediated by two isoforms of the estrogen receptor (ER) encoded by different genes, ERαand ERβ, which were cloned in 1986 and 1987, respectively. Both receptors function as ligand-dependent transcription factors to regulate gene expression according to the classical estrogen signalling pathway. However, estrogen signalling seems to be more complicated than the genomic pathway because several biological estrogen actions are too fast to be compatible with a transcriptional mechanism. Evidence has been accumulating indicating that not all of the physiological actions of estrogen can be explained according to a direct effect on gene transcription, and the involvement of signalling pathways related to cytoplasmatic proteins, growth factors and/or membrane-initiated responses has been reported. This mode of action has been termed non-classical, non-genomic or rapid effects of estradiol and it has been related to an increase in NO release, calcium homeostasis, cAMP accumulation or IGF pathway activation. However, the molecular mechanisms responsible are poorly understood. In this context, the existence of plasma membrane receptors has been proposed to explain the rapid actions of estrogen. What determines ERα targeting to the plasma membrane? The main question is, what is the role of these isoforms of ERα in/on the plasma membrane? It has been proposed that post-translational modifications of some ER proteins must occur to ensure targeting to the membrane, including palmitoylation, which could be related to facilitation of caveolin-1 binding, but more studies are needed to answer this question. Although the evidence suggests the existence of a close relationship between estrogen and sensitivity to the action of insulin, relatively few studies has attempted to solve the mystery exists about the molecular basis of this relationship in insulindependent tissues. Resolve these unknowns could have a major impact on long-term therapy, and that resistance to the action of insulin is the underlying cause of many diseases, for example, the aging female as Type 2 diabetes, cardiovascular disease circulatory, neurodegenerative diseases or some types of cancer. Recent data have revealed a surprising role for estradiol in regulating energy metabolism and opened new insights about the regulation of the intracellular insulin signalling and insulin secretion by ERα and ERβ. This new field of research promises radically to change our knowledge about the mechanism of actions of the estrogens and to contribute to understand better the therapeutic possibilities of the estrogens receptor in order to improve some aspects related to some menopause-relative diseases as insulin resistance, ictus, cancer and so on. The goal of these reviews is to highlight the important role that the fast or non-genomic estrogen actions has at different levels. In this way, Dr. Ripoll et al. show in their review that insulin release is controlled by estradiol due to the existence of ERα and ERβ in plasma membrane of β-cells, because 17α-estradiol regulates KATP channel activity and glucose-induced [Ca2+]i oscillations, eliciting changes in the activation of Ca2+-dependent transcription factors. Because an excess of white adipose tissue results in obesity and estrogens promote, maintain, and control the typical distribution of body fat and adipose tissue metabolism through still unknown mechanisms, Dr. Pallottini et al. show in their review the role of estrogens in adipose tissue differentiation and in the protection against the onset of obesity, and in this way they explain the underlying molecular mechanisms mediated by estrogen receptor isoform ERα and ERβ. Dr. Alonso and Dr. Gonzalez provide some evidences that suggest the existence of a narrow interrelation between the nongenomic action of estrogens and insulin sensitivity. The resolution of the unknown questions about the molecular mechanism of this interrelation would be able to have a great long-term therapeutic repercussion in several associated pathologies to the female aging, because insulin resistance could be the underlying cause of some of them. Finally, Dr. Gonzalez et al. analyzed present and future ways of the possible molecular mechanism involves in the neuroprotective effect of estrogens on brain. The relationship between insulin resistance states and neurodegenerative diseases associated with aging in females, and the cross-talk between estradiol and proteins includes in the IRS-1/PI3-k/Akt and IGF-1- IR signalling pathways in brain, will lead to a more complete understanding of the precise mechanism underlying estradiolmediated neuroprotection.