Structural and functional organization of the adenylyl cyclase signaling mechanism of insulin-like growth factor 1 revealed in the muscle tissue in vertabrates and invertebrates

Based on the earlier discovered by the authors adenylyl cyclase signaling mechanisms (ACSM) of action of insulin and relaxin, the study was performed of the presence a similar action mechanism of another representative of the insulin superfamily--the insulin-like growth factor 1 (IGF-1) in the muscle tissues of vertebrates (rat) and invertebrates (mollusc). For the first time there was detected participation of ACSM in the IGF-1 action, including the six component signaling cascade: receptor tyrosine kinase --> G(i)-protein (betagamma-dimer) --> phosphatidylinositol-3-kinase (PI-3-K) --> protein kinase Czeta (PKCzeta) --> G(-)protein --> adenylyl cyclase. By this mechanism structural-functional organization at postreceptor stages, in coincides completely with the mechanism of insulin and relaxin, which we revealed in rat skeletal muscle. In smooth muscle of the mollusc Anodonta cygnea this ACSM of action of IGF-1 has only one difference--the protein kinase C included in this mechanism is represented not by PKCzeta isoform, but by another isoform close to PKCepsilon of the vertabrate brain. Earlier we revealed the same differences in muscle of this mollusc in the ACSM of action of insulin and relaxin.     

Restoration of hypothalamic signaling systems as a cause of improved metabolic parameters in rats with neonatal diabetes model during treatment with bromocriptine mesylate

One approach to correction of diabetes mellitus 2 type (DM2) and its complications is the use of bromocriptine mesylate (BCM), a selective agonist of the dopamine receptor type 2 (DA₂R). However, the effectiveness and mechanisms of the action of BCM in the treatment of severe forms of DM2 forms currently not understood. The purpose of this study was to investigate the influence of 4-week treatment of male rats with neonatal DM2 model using BCM (300 mg/kg daily) on their metabolic parameters and on the activity of the adenylyl cyclase signaling system (ACSS) in the hypothalamus. Exposure to BCM restored glucose tolerance and glucose utilization by exogenous insulin, normalized lipid metabolism, and lowered triglycerides and atherogenic cholesterol levels, which are elevated in DM2. In the hypothalamus of diabetic rats treated with BCM, the regulation of ACSS by agonists of melanocortin receptors type 4 (MC₄R), DA₂R, and serotonin 1B-subtype receptors and expression of the Mc4r gene encoding MC₄R were restored. Furthermore, BCM treatment did not influence the insulin levels in the blood and its production by pancreatic β-cells. The data indicate that the use of BCM to correct severe forms of experimental DM2 holds promise and show that the therapeutic potential of this drug is based on its ability to restore signaling systems of the hypothalamus that are sensitive to monoamines and peptides of the melanocortin family, which are responsible for the control of energy metabolism and insulin sensitivity.     

QS-type bacterial signal molecules of nonpeptide origin

This review classifies and analyzes the literature data on bacterial autoinducers (AI), the signal molecules produced and secreted by bacterial cells and responsible for intercellular communication (quorum sensing, QS). The most important families of nonpeptide AI are discussed, including N-acyl homoserine lactones, derivatives of 2-methyl-2,3,4,5-tetrahydroxy tetrahydrofuran, indole and quinoline derivatives, and adrenalinerelated compounds. The data is provided on the intracellular and membrane receptors specifically binding to AI, as well as on the effector systems that are activated by AI and mediate their regulatory effects. The possible role of some vertebrate hormones (adrenergic agonists, serotonin, etc.) as AI and their effect on bacterial activity are discussed. The data are presented suggesting a high efficiency of AI-based antibacterial preparations, which selectively disrupt the bacterial information network and thus suppress bacterial infections.     

Using peptide strategy for study functions and structure of signal proteins with enzymatic activity

The peptide strategy, a new direction of molecular endocrinology, includes the synthesis of peptides corresponding to functional regions of signal proteins, the use of the peptides for study of the molecular mechanisms of transduction of hormonal signal into cell ant the development of selective regulators of hormonal signaling systems on the basis of these peptides. The peptide strategy is used for study a wide spectrum of the proteins, components of signal systems, the proteins possessing the catalytic activity in particular, such as tyrosine kinases receptors, the enzymes generating the second messengers, serine/threonine protein kinase, phosphatases. In the first time in the review the data concerning the synthetic peptides, derivatives of the primary structure of proteins with the enzymatic activity, their application for study of the structural-functional organization and the molecular mechanisms of action of signal proteins, and the construction of regulators of fundamental cell processes on the basis of these peptides are analyzed and summarized.