Progress in Physiological Science

A summary of literature data and the published results of our research show that in natural water bodies of the Earth – freshwater reservoirs (Lake Baikal, the Volga River), and lakes and seas with varying salinity (Lake Balkhash, the Caspian Sea, the Black Sea, the White Sea, the Barents Sea, and the Sea of Japan) – an increase in Na⁺ concentration from 0.18 mmol/L to 468 mmol/L is accompanied by an increase in K⁺ concentration from 0.025 mmol/L to 11.5 mmol/L (R² = 0.986, p < 0.001). In the internal fluids (blood serum, hemolymph) of hundreds of studied multicellular animal species – including mollusks, fish, amphibians, reptiles, birds, mammals, and humans – a similar pattern was observed: the K⁺/Na⁺ ratio remains constant, even as Na⁺ concentration increases from 15.9 mmol/L to 468 mmol/L and K⁺ concentration from 1.3 mmol/L to 15 mmol/L (R² = 0.832, p < 0.001). An almost complete match has been found between the K+/Na+ ratio constant in the internal fluids of living organisms and in the surrounding aquatic environment of the non-living nature. These findings indicate the constancy of the K⁺/Na⁺ ratio in the internal fluids of multicellular organisms and in the natural aquatic environments they inhabit. The revealed patterns are of fundamental importance for understanding the physiological principles of water-salt homeostasis. Deviations from standard physiological values of the K⁺/Na⁺ ratio are associated with various pathological conditions in humans.

Continuous renewal of body tissues is the key to maintaining the constancy of their function throughout a person'slife. Irreversible fading of tissue renewal processes over time underlies the development of age-associated diseases and determines the aging process. In addition, the development of socially significant diseases such as metabolic syndrome, type 2 diabetes, osteoporosis and many others is associated with the impaired tissue renewal. Postnatal stem cells play a decisive role in the process of tissue renewal and their adaptation to changing conditions. At the same time, a constant balance is maintained between the rate of cell growth and death throughout life. Disruption of this balance can lead to the development of both degenerative processes and oncological diseases. Therefore, the activity of stem cells is placed under strict control of the nervous and endocrine systems of the body. Despite the wide range of hormones and neurotransmitters acting on stem cells, the spectrum of intracellular signals that transmit information is extremely limited. Universal systems of second messengers generate unique cellular responses to different stimuli using specialized systems of signal tuning and modulation. One of the second messengers that ensure the transmission of intracellular signals is cyclic AMP synthesized by adenylate cyclase. This signaling pathway includes G protein-coupled receptors (GPCRs), various isoforms of adenylyl cyclases, as well as a wide range of scaffold and effector proteins. Working together, they ensure focusing of the cAMP signal and implement programs either to maintain stemness or, conversely, to trigger differentiation in various directions. The aim of our review is to provide a comprehensive view on the organization and compartmentalization of cAMP signaling in stem cells, as well as its participation in the regulation of the processes of maintaining the stemness and inducing differentiation in various directions.

The formation of extracellular (free, serum, soluble, and circulating) forms of receptors can occur through mechanisms of proteolytic shedding, alternative mRNA splicing, capping followed by endocytosis, aggregation of heterodimers, and release of receptors from extracellular vesicles (microvesicles and exosomes). Free forms of receptors, in addition to blood, have been identified in cerebrospinal, synovial, and lacrimal fluids, nasal secretions, urine, and in vitro cell cultures. The physiological role of free receptors is to ensure an adequate immune response of immunocompetent cells in the paracrine space environment, functional cell activity (activation, proliferation, apoptosis, secretion, cytokine synthesis), regulation of blood transport protein activity, and cell contact interaction. An increase in the concentration of extracellular receptor molecules has been identified in Arctic residents during the polar night, during short-term general cooling, and in various pathological processes. The prognostic and diagnostic significance of free receptors of immunocompetent cells has been established, and the dynamics of their content depending on the localization and stage of the disease has been shown. An excessive increase in the content of circulating receptors is associated with suppression of the immune response, a deficiency of phagocytic defense, a decrease in the clearance of circulating immune complexes, and activation of the synthesis of IgE, IL-10, and antibodies with an increase in the activity of blood cell aggregation reactions. The article presents current data on the functional role of free receptor molecules, circulating complexes in the extracellular space, the ratio of free and membrane receptors, the relationship between soluble receptors and their substrate, and the concentrations of cytokines and free cytokine receptors in the intercellular environment. The necessity of developing physiological limits for the concentration of free receptor molecules, identifying the causes of receptor release into the environment, and studying the mechanisms of accumulation of soluble forms of receptors is demonstrated.