The aim of this work was to verify the possibility of interactions between the human TRH receptor (an integral membrane protein which belongs to family 1 of G-protein coupled receptors) and TRH-like peptides presented in the prostate gland. These peptides are char
acterized by substitution of basic amino acid histidine (related to authentic TRH) for neutral or acidic amino acid, such as glutamic acid, phenylalanine, glutamine or tyrosine. The physiological function of TRH-like peptides in peripheral tissues is not precisely known. However, according to our recent experiments, we assume the existence of a local hormona
l network formed by TRH-like peptides and TSH in the prostate gland. The network can be associated with circulating thyroid and steroid hormones, and may represent a new regulatory mechanism influencing the proliferative ability of prostatic tissue. A similar network of authentic TRH and TSH was already found in the gastrointestinal tract. The experimentally determined 3D-structures of human TRH receptor
(hTRHr) and TRH-like peptides are not available. From this point of view we used de novo modeling procedures of G-protein coupled receptors on an automated protein modeling server used at the Glaxo Wellcome Experimental Research (Geneva, Switzerland). 3D-s
tructures of TRH-like peptides were determined with a computer program
CORINA (written by the team of J. Gasteiger, Computer-Chemie-Centrum and Institute for Organic Chemistry, University of Erlangen-Nurenberg, Germany). The generated PDB files with 3D-coordinates were visualized with Swiss-Pdb Viewer Release 3.51 (Glaxo Wellcome). From recent results it is evident that polar amino acids belonging to the extracellular terminus of hTRHr transmembrane regions can participate in interactions between TRH and hTRHr. There is no direct evidence that TRH-like peptides interact with the presented hTRHr model. On the contrary, with respect to the similar 3D-shape and the identity of terminal amino acids, it appears that these interactions are highly
probable as well as the nearly 100 % cross-reactions between TRH or TRH-like peptides and antibody specific against authentic TRH. Closed terminal amino acids (pyroglutamic acid and proline-amide) of TRH or TRH-like peptides are important for these interactions. Desamido-TRH or glutamyl metabolites will be repelled by the negative potential of
ASP195 (E: D93) and GLU298 (G: E137).
There is considerable evidence linking alcohol consumption and sedation and TRH in the brain septum. Moreover, innate septal TRH concentration is inversely related to the degree of ethanol preference. Recently we demonstrated in rats that four-week ethanol drinking increased the septal TRH content by 50 %. We had shown previously that ethanol induces neuronal swelling, which is known to evoke the secretion of hormones, peptides and amino acids from various types of cells. We have therefore explored the effect of hyposmotic medium and of 80 and 160 mM ethanol and 80 mM urea (both permeant molecules) in isosmotic and hyperosmotic (preventing cell swelling) media on the in vitro release of TRH by the rat septum. Lowering medium osmolarity resulted in a hyposmolarity-related increase in TRH secretion. Both ethanol and urea stimulated TRH release only in isosmolar solution. Our data indicate that ethanol in clinically relevant concentrations can induce TRH release from the septum by a mechanism involving neuronal swelling., J. Kučeorvá, V. Štrbák., and Obsahuje bibliografii
TRH-like peptides are characterized by substitution of basic amino acid histidine (related to authentic TRH) with neutral or acidic amino acid, like glutamic acid, phenylalanin e, glutamine, tyrosine, leucin, valin, aspartic acid and asparagine. The presence of extrahypothalamic TRH-like peptides was reported in peripheral tissues including gastroin testinal tract, placenta, neural tissues, male reproductive system and certain endocrine tissues. Work deals with the biological function of TRH-like peptides in different parts of organisms where various mechanisms may serve for realisation of biological function of TRH-like peptides as negative feedback to the pituitary exerted by the TRH-like peptides, the role of pEEPam such as fertilization-promoting peptide, the mechanism influencing the proliferative ability of prostatic tissues, the neuroprotective and antidepressant function of TRH-like peptides in brain and the regulation of thyroid status by TRH-like peptides., R. Bílek, M. Bičíková, L. Šafařík., and Obsahuje bibliografii a bibliografické odkazy