Uspehi fiziologičeskih nauk

Post-traumatic stress disorder is a mental disorder that is closely associated with dysfunction of the hypothalamic-pituitary-adrenal axis, and for its development is required the experience of a traumatic event that causes negative emotions and memories that persist for quite a long time. The likelihood of development of post-traumatic stress disorder is influenced both environmental factors, and genetic and epigenetic characteristics of the body. In this case epigenetic modifications act as dynamic biomarkers (“nanotags”) of the impact of the environment on the genome (epigenome), which can, under certain conditions, disappear or remain not only in an individual directly exposed to psychogenic trauma, but also transmitted over a number of generations. Review focuses on the possible mechanisms of intergenerational and transgenerational inheritance of the biological effects of post-traumatic and stress-related disorders.

The regulatory effects of luteinizing hormone (LH) and chorionic gonadotropin (CG) are realized through the activation of the G-protein coupled LH/CG receptor (LH/CG-R). The result of this is the activation of various types of G proteins, which leads to stimulation (G_s) or inhibition (G_i) of the cAMP-dependent pathway and stimulation of calcium signaling (G_q/11, G_i), and the recruitment of β-arrestins, which prevent G protein signaling through receptor internalization and downregulation, but can also activate the mitogen-activated protein kinase cascade. Despite a certain similarity in the effects of LH and CG, there are differences between them both in efficiency and in the pattern of regulation of LH/CG-R. This is a consequence of differences in the affinity of LH and CG to the orthosteric site of the receptor, as well as differences at the level of allosteric regulation of the receptor, which is due to the presence of a C-terminal extension in the β-subunit of CG, including sites for O-glycosylation, and the variability of N-glycosylation of α- and β-subunits of gonadotropins. Moreover, the number of N-glycans, the degree of their branching and charge differ, which leads to different efficiency of activation of intracellular cascades, affecting the physiological response of the reproductive system to gonadotropins. Of great importance is the formation of homodi(oligo)meric complexes of LH/CG-R and its heterocomplexes with the follicle-stimulating hormone receptor, where protomers allosterically influence the efficiency of LH/CG-R activation and the bias of signal transduction. Taking into account the large number of allosteric sites in LH/CG-R, the development of low-molecular allosteric regulators is underway, including agonists based on thieno[2,3-d]-pyrimidine and peptides derived from the cytoplasmic loops of LH/CG-R. These regulators can become prototypes of drugs for correcting the functions of the reproductive system. This review is devoted to the analysis of data on the similarities and differences in the signaling and physiological effects of gonadotropins with LH activity, the role of allosteric mechanisms in this, and the prospects for creating allosteric regulators of LH/CG-R.

The membrane T1R taste receptor family interacts with sweet substances – carbohydrates, artificial sweeteners and some amino acids. An important result of research in the 21st century was the discovery of abundant expression of these receptors outside of the oral cavity, mainly in cells actively involved in metabolic processes: enteroendocrine cells of the intestine, pancreatic β-cells, adipose and bone tissue, etc. This review integrates and analyzes current data on the role of extraoral T1R receptors in the regulation of metabolism, cell growth and differentiation, which is achieved through modulation of hormone secretion (insulin, GLP-1, GIP), activity of membrane transporters and cell growth and proliferation factors. T1R mediated cellular responses to nutrients, mechanisms of signal transduction, effects on inositol triphosphate, cAMP and intracellular Ca²⁺ levels, stimulatory effects on glucose transporters SGLT1 and GLUT2, effects on mTOR and hormone secretion are described. The interaction of membrane receptor mechanisms and metabolic detection of glucose by the ATP/ADP ratio in the cell cytoplasm is also discussed. Putative evolutionary adaptation of metabolic processes related to nutrition and manifested in polymorphism of genes encoding T1R proteins is presented. It is suggested that extraoral taste receptors for sweet substances and amino acids may be a target for therapeutic interventions in obesity, hyperglycemia, insulin resistance, and hepatosteatosis.