M. N. Pertseva

On the tyrosine kinase mechanism of the novel effect of insulin and insulinlike growth factor I: Stimulation of the adenylyl cyclase system in muscle tissues

For the first time, insulinlike growth factor I (IGF-I), like insulin (Pertseva et al., Comp Biochem Physiol 112: 689-695, 1995), was shown to exercise a GTP-dependent stimulating action on adenylyl cyclase (AC; EC 4.6.1.1.) activity in the muscle tissues (membrane fraction) of mammal (rat) and mollusc (Anodonta cygnea). By studying the mechanism of the effect of peptides with selective inhibitors of tyrosine kinase activity, tyrphostin 47 (RG50864, 3,4-dihydroxy-alpha-cyanothiocinnamamide) and genistein (4,5,7-trihydroxyisoflavone), it was found that receptor tyrosine kinase is involved in this action. The data obtained suggest that the stimulating effect of insulin and IGF-1 is produced via the following signalling system: receptor tyrosine kinase --> stimulatory G-protein --> AC. Thus, the existence of a novel signalling pathway of transduction of signals generated by insulin and related peptides was hypothesised.

Conservatism of the Insulin Signaling System in Evolution of Invertebrate and Vertebrate Animals

The insulin system including hormone insulin and signaling mechanisms realizing a wide spectrum of its regulatory effect is one of the major systems in the animals and human organism. At present the history of origin of this regulatory system in the course of evolution starts to be formed. There are grounds to believe that it appeared in unicellular eukaryotes, developed in multicellular ones, and achieved significant perfection in higher vertebrates. This paper analyzes the structural-functional organization of insulin-like peptides, their receptors, and the corresponding signaling mechanisms in four types of invertebrates (sponges, nematodes, molluscs, arthropods) in comparison with those in higher vertebrates. There is revealed evolutionary conservatism in the common structural-functional organization of insulin-like peptides of invertebrates and insulin of vertebrate animals; receptors of insulin-like peptides of invertebrates and receptors of insulin and insulin-like growth factor 1 of vertebrates that have tyrosine kinase activity; the insulin-like signaling systems including signaling blocks, similar by their primary structure in invertebrate and vertebrate animals (IRS-proteins, G-proteins, adenylyl cyclase, protein kinases A and C, etc.). The point of view is put forward that the conservatism of the functional blocks of the insulin system does not mean the absence of evolutionary changes of this system as a whole. Examples of such evolutionary changes leading to complication of the insulin system organization at supramolecular and cellular levels and to an increase of efficiency of its functioning are presented.

Study of the Functional Organization of a Novel Adenylate Cyclase Signaling Mechanism of Insulin Action

In this study we continued decoding the adenylate cyclase signaling mechanism that underlies the effect of insulin and related peptides. We show for the first time that insulin signal transduction via an adenylate cyclase signaling mechanism, which is attended by adenylate cyclase activation, is blocked in the muscle tissues of the rat and the mollusk Anodonta cygnea in the presence of: 1) pertussis toxin, which impairs the action of the inhibitory GTP-binding protein (Gi); 2) wortmannin, a specific blocker of phosphatidylinositol 3-kinase; and 3) calphostin C, an inhibitor of different isoforms of protein kinase C. The treatment of sarcolemmal membrane fraction with cholera toxin increases basal adenylate cyclase activity and decreases the sensitivity of the enzyme to insulin. We suggest that the stimulating effect of insulin on adenylate cyclase involves the following stages of hormonal signal transduction cascade: receptor tyrosine kinase → Giprotein (βγ) → phosphatidylinositol 3-kinase → protein kinase C (ζ?) → Gsprotein → adenylate cyclase → cAMP.

Adenylyl cyclase signaling mechanisms of relaxin and insulin action: Similarities and differences

The adenylyl cyclase signaling mechanism (ACSM) of relaxin H2 action was discovered and deciphered in mammalian muscles. A study of signaling blocks involved in ACSM of relaxin in comparison with that of insulin previously detected showed a close similarity throughout the post‐receptor signaling chain of both hormones. The inhibitory action of tyrosine kinase blockers on the hormone AC activating effect indicates that the relaxin receptor involved in ACSM is likely to be of the tyrosine kinase type. However, a recent discovery of a relaxin receptor with serpentine architecture leaves open the question concerning the existence of receptor of the tyrosine kinase type. The structural‐functional organization of the ACSM due to the action of relaxin—shown here for the first time—can be presented as the following signaling sequence: relaxin receptor ⇒ Gi protein (βγ‐dimer) ⇒ phosphatidylinositol 3‐kinase ⇒ protein kinase Cζ ⇒ Gs protein ⇒ adenylyl cyclase. According to our hypothesis, the regulatory action of the insulin superfamily peptides on cell processes (proliferation, apoptosis, and metabolism) is mediated via ACSM.

A novel, adenylate cyclase, signaling mechanism of relaxin H2 action

Abstract: For the first time, the adenylate cyclase signaling mechanism (ACSM) of the action of relaxin H2 was revealed and deciphered in human and rat muscle tissues. The comparative study of signaling blocks forming the ACSM of relaxin and insulin (discovered earlier) showed that the postreceptor signaling chain of relaxin coincides with that of insulin. However, the type of relaxin receptor involved in ACSM remains obscure. Currently, the ACSM of relaxin may be represented as a signaling cascade: receptor ⇒ Gi protein (βγ‐dimer) ⇒ phosphatidylinositol 3‐kinase (PI3K) ⇒ protein kinase Cζ (PKCζ) ⇒ Gs protein ⇒ adenylate cyclase.

Signal transduction systems in prokaryotes

The main components of chemosignaling systems of prokaryotes are multifunctional receptor molecules that include both sensor domains specifically recognizing external signals and effector domains converting these signals into an adequate cell response. This review summarizes and analyzes data on structural-functional organization, molecular mechanisms of action, and regulation of receptor forms of histidine kinases, adenylyl kinases, diguanylyl cyclases, and phosphodiesterases. These enzymes have been shown to be precursors of the receptor and effector components of the eukaryote hormonal signaling systems. This confirms the hypothesis developed by the authors about formation of the main archetypes of chemosignaling systems at the early evolution stages and about the evolutionary relationship of the signaling systems of prokaryotes and eukaryotes.

Relaxin Adenylyl Cyclase System of Pregnant Women with Diabetes: Functional Defects in Insulin and Relaxin Adenylyl Cyclase Signaling Systems in Myometrium of Pregnant Women with Type 1 Diabetes

Abstract: The study was conducted to reveal the functional disturbances in two novel insulin and relaxin adenylyl cyclase signaling mechanisms (ACSMs). It was shown for the first time that in myometrium of pregnant women with insulin insufficiency the functional defects of Gs‐protein‐AC coupling in insulin‐ and relaxin H2‐regulated AC systems were developed. As a result, the sensitivity of the signaling systems to both hormones and potentiation of their AC effects by guanine nucleotides were markedly decreased compared with that in control group. These functional defects in ACSM may lead to violation of the process of insulin and relaxin signal transduction.

Functional Coupling of Hormone Receptors with G Proteins in the Adenylate Cyclase System of the Rat Muscle Tissues and Brain under Conditions of Short-Term Hyperglycemia

The sensitivity of components of the adenylate cyclase signaling system (heterotrimer G proteins and adenylate cyclase enzyme) to the regulatory effects of hormones mediated through G proteins (stimulatory effect of isoproterenol and relaxin and inhibitory effects of somatostatin) was decreased in the myocardium of hyperglycemic rats under conditions of transitory hyperglycemia caused by intravenous glucose and in hyperglycemia associated with insulin insufficiency in 24-h type 1 streptozotocin-induced diabetes mellitus. Changes in hormone sensitivity of the adenylate cyclase system were tissue-specific: clearly manifest in the myocardium, minor in skeletal muscles, and virtually absent in the brain of hyperglycemic rats. The main disorders of this system in the myocardium were observed at the stage of hormone receptor coupling with G proteins, which was seen from reduced stimulatory effect of GppNHp on adenylate cyclase activity and attenuation of the regulatory effect of hormones on adenylate cyclase enzyme and G proteins functionally coupled with it.

Involvement of adenylyl cyclase signaling mechanism in insulin and IGF-I coregulation of fundamental cell processes.

Abstract: The discovery of the adenylyl cyclase signaling mechanism (ACSM) of insulin and related peptides allows for advancing the hypothesis of its participation in regulatory action on cell growth, apoptosis, and metabolism. The following evidences were obtained: (1) The order of efficiency of insulin and IGF‐I growth‐promoting action and their antiapoptotic effect coincides with that of the peptide‐activating action on AC. (2) The growth‐promoting and antiapoptotic effects of insulin and IGF‐I are distinctly reproduced by cAMP. (3) The anabolic effects of insulin and IGF‐I activation on glycogen synthesis and the pentosophosphate pathway are inhibited by cAMP.

Regulation of the activity of adenylate cyclase and protein kinase a of the infusorians Dileptus anser and Tetrahymena pyriformis by biogenic amines and peptide hormones.

The hormone-sensitive adenylate cyclase (AC) system is one of the key signal systems involved in the transduction of hormonal signals in eukaryotic cells. The structural and functional organization of the AC system of higher eukaryotes has been studied sufficiently well, whereas the structure and mechanisms of function of lower eukaryotes are poorly understood. At the same time, the AC system of lower eukaryotes is an evolutionally more ancient signal system, and its study is a promising method of studying the evolution of the hormonal signaling systems.