Membrane G protein-coupled receptors (GPCRs) are key components of most eukaryotic signaling systems, transducing external signals to intracellular effector proteins. Activation of GPCRs occurs ...through the specific binding of ligands of different nature to their orthosteric site. However, regulation of the affinity of an orthosteric agonist for the receptor, control of its effectiveness, and selection of the preferentially activated intracellular signaling cascade is carried out using allosteric mechanisms. This is due to the presence in GPCRs of many allosteric sites, which differ in structural and functional organization and topology in the receptor molecule, and are located in all its functional subdomains. The endogenous regulators of these sites are simple ions (Na+, Zn2+, Mg2+, Ca2+, Cl– and others), lipids (cholesterol, phospholipids, steroids), amino acids and their derivatives, polypeptides, as well as signaling proteins that form functionally active complexes with GPCRs (G proteins, β-arrestins, RAMPs), and autoantibodies to the extracellular regions of GPCRs. Based on pharmacological activity, ligands of allosteric sites of GPCRs are divided into positive, negative or silent modulators of the effects of orthosteric agonists, as well as full and inverse agonists or neutral antagonists, which affect the basal activity of the receptor in the absence of an orthosteric agonist, although combining the properties of a modulator and an agonist is also possible. The multiplicity of allosteric sites and allosteric regulators, complex interactions between them, and the involvement of allosteric mechanisms in the formation of receptor complexes play a key role in fine-tuning the functional activity of signaling cascades, in biased agonism, and predetermine the processes of receptor desensitization and the fate of the receptor complex after hormonal signal transduction. The review summarizes and analyzes current concepts and new trends in the field of studying the allosteric regulation of GPCRs, the localization and functional role of allosteric sites, and their endogenous and synthetic ligands. As an example, synthetic allosteric regulators of the receptors of thyroid-stimulating and luteinizing hormones, as potential drugs for the correction of endocrine disorders, are discussed in detail.
Activity in the peripheral components of the hypothalamo-hypophyseal-gonadal and -thyroid axes is regulated by hypophyseal hormones – gonadotropins and thyrotropic hormones (thyroid-stimulating ...hormone, TSH), which are secreted by specialized cells in the adenohypophysis. Luteinizing hormone (LH) and its homolog chorionic gonadotropin (CG) realize their steroidal effects by binding to LH/CG receptors on the surfaces of Leydig cells in the testes and theca cells and granulosa cells in mature follicles in the ovaries. Follicle-stimulating hormone (FSH) binds FSH receptors on Sertoli cells in the testes and granulosa cells in primordial and maturing follicles in the ovaries, controlling the processes of folliculogenesis, spermatogenesis, and steroidogenesis. TSH, via activation of TSH receptors, stimulates the synthesis of thyroid hormones by thyrocytes in the thyroid gland. Gonadotropins (LH, CG, and FSH) and TSH, which bind with high affinity to the extracellular domains of specific G protein-coupled receptors, directly activate various signal cascades operating via different types of G-proteins and β-arrestins. Recombinant gonadotropins and gonadotropins extracted from natural sources and used for the treatment of reproductive dysfunction and as assisted reproduction technologies have a number of drawbacks, which has led to the development of peptide and low molecular weight regulators of LH/CG and FSH receptors which interact with allosteric sites on the transmembrane or cytoplasmic domains of the receptors. Wide perspectives in the regulation of reproductive functions and the control of fertility are opened up by the use of adipokines, peptides of the insulin and relaxin families, and the antidiabetic drug metformin, which not only regulate and modify the responses of the gonads to gonadotropins, but also themselves influence steroidogenesis and gamete maturation. In the case of TSH receptors, the most acute problem is that of reversing increases in their activity in autoimmune and oncological diseases of the thyroid gland and in endocrine ophthalmopathy. The greatest potential in this direction lies in the ongoing development of low molecular weight inverse agonists and neutral antagonists, which interact with an allosteric site located in the transmembrane domain of the TSH receptor. The present review addresses contemporary advances in the development and study of endogenous and synthetic regulators and modulators of gonadotrophic and TSH receptors, along with their influences on the peripheral components of the hypothalamo-hypophyseal-gonadal and -thyroid axes.
Penetration of coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), the cause of the COVID-19 pandemic, into cells requires interaction of the surface spike S protein of the ...virus with extracellular domain of the membrane-bound form of angiotensin-converting enzyme type 2 (ACE2). This enzyme, the key component of the renin-angiotensin system, is responsible for the synthesis of angiotensin-(
1
–
7
), which has vasodilator and autoimmune properties, from angiotensin II, a powerful vasoconstrictor, whose synthesis is catalyzed by angiotensin-converting enzyme (ACE), a functional antagonist of ACE2. After site-specific hydrolysis by transmembrane serine protease TMPRSS2 in infected cells, viral S protein specifically binds ACE2, which is the trigger for internalization of the virus into cells by endocytosis. Suppression of this process with drugs inhibiting TMPRSS2 protease and impairing the interaction of S protein with ACE2 prevents infection and is therefore a potential approach to the treatment and prophylaxis of COVID-19. This mechanism of penetration into cells is also used by SARS-CoV virus, the pathogen of atypical pneumonia, which is related to SARS-CoV-2. Treatment of patients with arterial hypertension and diabetes mellitus using ACE inhibitors and angiotensin receptor blockers, statins, and various antidiabetic drugs generally increases the expression and activity of ACE2, which increases the risk of infection with SARS-CoV-2 and worsens the outcome of disease. During the process of infection, the virus forms a complex with ACE2 and decreases the quantity of ACE2 on the cell surface, impairing ACE2-dependent physiological processes, and this is one of the causes of acute respiratory distress syndrome and heart failure in COVID-19 patients. The present review analyzes the functional role of ACE2 in the infection of cells by SARS-CoV-2 and SARS-CoV, and the molecular mechanisms of this process and its pathophysiological consequences are discussed.
Abstract
Abstract
The functions of hypothalamic-pituitary-thyroid axis are attenuated in type 1 diabetes mellitus due to insulin deficiency. The use of intranasally administered insulin is of ...considerable interest for treatment of diabetes and cognitive disorders, but its effect on the thyroid system has not been investigated yet. We studied the influence of long-term treatment with intranasal insulin on the hypothalamic-pituitary-thyroid axis of nondiabetic rats and diabetic animals with streptozotocin models of acute and mild type 1 diabetes mellitus. This treatment was carried out for 28 days in acute (daily does of 0.3, 0.6, and 1.5 IU of insulin per rat) and for 135 days in mild diabetes (daily dose of 0.45 IU/rat). Nondiabetic rats were treated in a similar manner. Intranasal insulin in both models of diabetes resulted in the improvement of thyroid status; manifested as increase of thyroid hormones levels and restoration of response to thyroliberin. In acute diabetes, a daily dose of 0.6 IU/rat was the most effective. Twenty eight days treatment of nondiabetic rats with intranasal insulin at a dose of 0.3 IU/rat resulted in a significant increase of free and total thyroxine levels. Longer treatment of rats with mild diabetes and nondiabetic animals significantly increased thyrotropin level. Thus, long-term intranasal insulin treatment restored the hypothalamic-pituitary-thyroid axis function in type 1 diabetes, but led to a significant increase in the thyrotropin level, which must be considered when designing a strategy for the use of intranasal insulin in clinical applications.
The development of low-molecular-weight antagonists of thyroid-stimulating hormone (TSH) receptor is a promising trend in the treatment of autoimmune hyperthyroidism. We studied the effect of ...thieno2,3-d-pyrimidine derivative TPY1 on TSH-stimulated synthesis of thyroid hormones in the culture of FRTL-5 thyrocytes and on thyroliberin-stimulated production of thyroid hormones in rat blood. Preincubation of FRTL-5 cells with TPY1 suppressed the stimulatory effect of TSH on the synthesis of thyroxine and triiodothyronine. Intraperitoneal injection of TPY1 in a dose of 25 mg/kg reduced thyroliberin-stimulated levels of thyroid hormones in the blood and inhibited the expression of genes encoding thyroid peroxidase, thyroglobulin, and Na
+
/I— cotransporter responsible for thyroxine synthesis. In the absence of thyroliberin stimulation, TPY1 did not affect the levels of thyroid hormones and expression of thyroidogenesis genes. Thus, a new TPY1 antagonist of TSH receptor can be a prototype of a drug for the treatment of autoimmune hyperthyroidism.
One of the key elements responsible for the thyroid response to thyroid-stimulating hormone (TSH) is the TSH receptor (TSHR), which belongs to the G protein-coupled receptor superfamily. Binding of ...TSH or stimulatory autoantibodies to the TSHR extracellular domain triggers multiple signaling pathways in target cells that are mediated through various types of G proteins and β-arrestins. Inhibitory autoantibodies, in contrast, suppress TSHR activity, inducing hypothyroid states. Activating mutations lead to constitutively active TSHR forms and can trigger cancer. Therefore, the TSHR is one of the key targets for the regulation of thyroid function and thyroid status, as well as correction of diseases caused by changes in TSHR activity (autoimmune hyper- and hypothyroidism, Graves’ ophthalmopathy, thyroid cancer). TSH preparations are extremely rarely used in medicine due to their immunogenicity and severe side effects. Most promising is the development of low-molecular allosteric TSHR regulators with an activity of full and inverse agonists and neutral antagonists, which are able to penetrate into the allosteric site located in the TSHR transmembrane domain and specifically bind to it, thus controlling the ability of the receptor to interact with G proteins and β-arrestins. Allosteric regulators do not affect the binding of TSH and autoantibodies to the receptor, which enables mild and selective regulation of thyroid function, while avoiding critical changes in TSH and thyroid hormone levels. The present review addresses the current state of the problem of regulating TSHR activity, including the possibility of using ligands of its allosteric sites.
—The formation and development of neurochemistry at the Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences (IEPhB RAS) is closely associated with the ...name of its founder, the outstanding Russian physiologist, Academician Leon Abgarovich Orbeli. Orbeli not only became the founder and ideological inspirer of a new field of physiological science—evolutionary physiology, but also assigned the greatest importance to the study of the chemical and cellular mechanisms of the functioning of the central nervous system, considering them the “core” of the implementation of many physiological functions in his works. His work was worthily continued by his disciples and followers, Academician Evgeny Mikhailovich Kreps and Corresponding Member Andrei Lvovich Polenov, one of the founders of modern neurochemistry and neuroendocrinology in Russia. At the heart of their scientific approach, in full agreement with the traditions laid down by L.A. Orbeli, is not a static analysis of biochemical and regulatory processes in neurons and glial cells, but the study of chemical interactions between nerve cells, between regions of the brain, and between the brain and visceral organs, which are constantly changing in ontogeny, phylogeny, when under the influence of various external and endogenous factors, and in pathological conditions. Only this approach can explain the subtle mechanisms of the functioning of individual neurons, the brain and the entire body as a whole, as well as identify the molecular causes of diseases of the nervous, endocrine and other systems. The creative heritage of L.A. Orbeli, E.M. Kreps and A.L. Polenov is the numerous scientific schools of neurochemists and neuroendocrinologists at IEPhB RAS and in other scientific institutions of Russia, which successfully develop the creative heritage of their teachers.
The so-called cafeteria diet (CD), rich in saturated fats and light fast-digesting carbohydrates, leads to obesity and is a risk factor for type 2 diabetes. Metformin (MF) is often used to correct ...diet-induced obesity, but in some patients, it elicits serious side effects, which requires dose reduction, including through its co-application with drugs potentiating MF effects. Intranasally administered insulin (INI), which
per se
has a restorative potential in the treatment of metabolic disorders, is a candidate for the role of such a drug. This work was aimed to study the efficacy of a 3-week combined course of MF (100 mg/kg/day, perorally) and INI (1.5 or 6.0 IU/kg/day) to correct metabolic and hormonal disorders in male rats with CD-induced obesity (CDIO). It was shown that in CDIO rats, the MF + INI combination normalized body weight and abdominal fat, as well as restored glucose homeostasis, lipid metabolism, basal and glucose-stimulated insulin and leptin levels. Compared to MF monotherapy, a combined course of MF + INI application more effectively restored insulin sensitivity, as assessed by a decrease in the insulin resistance index, and normalized glucose tolerance, as assessed by a decrease in AUC
0–120
, the integrated area under glucose concentration curves in the glucose tolerance test. The combination of MF with INI at a dose of 1.5 IU/kg/day normalized thyroidal status, disturbed in CDIO, while the combination of MF with INI at a dose of 6 IU/kg/day exacerbated the hypothyroid state, mainly due to hyperactivation of thyroid-stimulating hormone secretion and the development of thyroid resistance to this hormone. Thus, a combined course of MF with relatively low-dose INI, which has no negative effects on the thyroid axis, appears promising for correcting metabolic and hormonal indices in CDIO, including functional restoration of the thyroid system.
Type 1 and type 2 diabetes mellitus (DM) are known to increase the incidence of thyroid gland (TG) dysfunctions. The review addresses the literature data and our experimental results on the molecular ...mechanisms that underlie thyroid disorders under DM. Most important of these mechanisms are the attenuation of thyrocyte adenylyl cyclase signaling system sensitivity to thyroid-stimulating hormone, the decrease in the number of thyroid hormone receptors in peripheral tissues, and the decline in activity as well as changes in the ratio of different deiodinase forms in these tissues. Decreased activity of D2 deiodinases, which convert thyroxine into the active form of triiodothyronine, is associated with the development of insulin resistance, while decreased activity of D3 deiodinases, which catalyze inactivation of triiodothyronine in pancreatic β cells, suppresses insulin secretion and leads to insulin deficiency. Thus, both the excess and the deficiency of thyroid hormones can entail diabetic pathology. Identification of thyroid disorders is of utmost importance for elaborating novel approaches to treat and prevent thyroid diseases associated with type 1 and type 2 DM.
The insulin signal system of the brain plays a key role in regulating fundamental cellular process in neurons, and it controls metabolic processes in the CNS and the periphery. In hypothalamic ...neurons, the insulin signaling system interacts closely with other signal systems controlled by leptin, melanocortin peptides, dopamine, and serotonin, and is a key component of the signal network of the hypothalamus, integrating and transforming central and peripheral signals. Impairments to the insulin system of the brain lead to the development of central insulin resistance, which is one of the prime causes of type 2 diabetes mellitus (DM), metabolic syndrome, and Alzheimer’s disease. Timely restoration of the insulin system of the brain is an effective approach for the prophylaxis and treatment of type 2 DM and associated neurodegenerative diseases. This review analyzes and assesses published data and our own results on the structural-functional organization of the insulin signal system of the brain, impairments to insulin signaling in the CNS, and approaches to its restoration in type 2 DM.
PDF
