BACKGROUND: The mammalian Leukocyte Receptor Complex (LRC) chromosomal region may contain gene families for the killer cell immunoglobulin-like receptor (KIR) and/or leukocyte immunoglobulin-like receptor (LILR) collections as well as various framing genes. This complex region is well described in humans, mice, and some domestic animals. Although single KIR genes are known in some Carnivora, their complements of LILR genes remain largely unknown due to obstacles in the assembly of regions of high homology in short-read based genomes. METHODS: As part of the analysis of felid immunogenomes, this study focuses on the search for LRC genes in reference genomes and the annotation of LILR genes in Felidae. Chromosome-level genomes based on single-molecule long-read sequencing were preferentially sought and compared to representatives of the Carnivora. RESULTS: Seven putatively functional LILR genes were found across the Felidae and in the Californian sea lion, four to five genes in Canidae, and four to nine genes in Mustelidae. They form two lineages, as seen in the Bovidae. The ratio of functional genes for activating LILRs to inhibitory LILRs is slightly in favor of inhibitory genes in the Felidae and the Canidae; the reverse is seen in the Californian sea lion. This ratio is even in all of the Mustelidae except the Eurasian otter, which has a predominance of activating LILRs. Various numbers of LILR pseudogenes were identified. CONCLUSIONS: The structure of the LRC is rather conservative in felids and the other Carnivora studied. The LILR sub-region is conserved within the Felidae and has slight differences in the Canidae, but it has taken various evolutionary paths in the Mustelidae. Overall, the process of pseudogenization of LILR genes seems to be more frequent for activating receptors. Phylogenetic analysis found no direct orthologues across the Carnivora which corroborate the rapid evolution of LILRs seen in mammals.

• Klíčová slova
• KIR, LILR, Leukocyte Receptor Complex, carnivora, felids, long-read sequencing,
• MeSH
• Canidae * MeSH
• Carnivora * genetika   MeSH
• Felidae * MeSH
• fylogeneze MeSH
• genomika MeSH
• lachtani * MeSH
• leukocyty MeSH
• lidé MeSH
• Mustelidae * MeSH
• myši MeSH
• receptory imunologické genetika   MeSH
• receptory KIR genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory imunologické MeSH
• receptory KIR MeSH

The biological activity of cyanobacteria and their chemical components have been widely studied due to their blooms in eutrophic waters worldwide. The primary goal of this study was to determine if individual cyanobacterial species and mixtures of cyanobacteria collected from the environment contain compounds with the potential for interaction with signaling pathways of the aryl hydrocarbon receptor (AhR), androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR) and retinoid acid receptor (RAR). Cytotoxicity and specific toxic potencies of products of freshwater cyanobacteria were determined by use of in vitro reporter gene trans-activation assays. The testing included samples prepared from five selected single cyanobacterial species cultivated in laboratory and five complex cyanobacterial biomasses collected from blooms in surface waters in the Czech Republic. The results demonstrate estrogenic potencies of extracts of cyanobacterial biomasses. Among the laboratory single species, the extract of Planktothrix agardhii (intracellular metabolites) had a potency of estrogenic equivalents (EEQ) of 3.8 ng 17β-estradiol/g dw. The estimates of EEQs of samples prepared from complex cyanobacterial biomasses collected from freshwaters in the Czech Republic ranged from 19 to 2200 ng 17β-estradiol/g dw. Several samples prepared from the environmental cyanobacterial biomasses potentiated the androgenic potency of dihydrotestosterone. There was no dioxin-like, glucocorticoid or anti/retinoic activity observed for any of the extracts studied. Extracts of natural complex cyanobacterial biomasses exhibited greater and more frequent presence of compounds with specific modes of action, mainly estrogenic, and also greater cytotoxicity than extracts of single cyanobacterial species. The demonstrated estrogenic potency of the compounds present in complex cyanobacterial biomasses is of environmental relevance, and could potentially contribute to endocrine disruptive effects in aquatic ecosystems in case of great bloom densities.

• MeSH
• androgenní receptory metabolismus   MeSH
• bakteriální toxiny toxicita   MeSH
• biomasa MeSH
• biotest MeSH
• buněčné linie MeSH
• cytotoxiny toxicita   MeSH
• endokrinní disruptory toxicita   MeSH
• estrogeny toxicita   MeSH
• komplexní směsi toxicita   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mikrocystiny toxicita   MeSH
• nádorové buněčné linie MeSH
• receptory aromatických uhlovodíků metabolismus   MeSH
• receptory glukokortikoidů metabolismus   MeSH
• receptory kyseliny retinové metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• sinice chemie   MeSH
• techniky in vitro MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androgenní receptory MeSH
• bakteriální toxiny MeSH
• cytotoxiny MeSH
• endokrinní disruptory MeSH
• estrogeny MeSH
• komplexní směsi MeSH
• microcystin MeSH Prohlížeč
• mikrocystiny MeSH
• receptory aromatických uhlovodíků MeSH
• receptory glukokortikoidů MeSH
• receptory kyseliny retinové MeSH
• receptory pro estrogeny MeSH

The structural characterization of the insulin-insulin receptor (IR) interaction still lacks the conformation of the crucial B21-B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

• Klíčová slova
• active conformation, complex, insulin, insulin receptor, isothermal titration microcalorimetry, molecular dynamics,
• MeSH
• fenylalanin MeSH
• fibroblasty metabolismus   MeSH
• inzulin analogy a deriváty   chemie   genetika   metabolismus   MeSH
• konformace proteinů MeSH
• krystalografie rentgenová MeSH
• kultivované buňky MeSH
• lidé MeSH
• lymfocyty metabolismus   MeSH
• molekulární modely MeSH
• mutace MeSH
• myši knockoutované MeSH
• myši MeSH
• potkani Wistar MeSH
• receptor inzulinu chemie   metabolismus   MeSH
• substituce aminokyselin MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fenylalanin MeSH
• inzulin MeSH
• receptor inzulinu MeSH

In the recent years, a therapeutic potential of disulfiram (Antabuse) complex with copper, as an anticancer drug, was recognized towards several cancer cell lines. The proteasome was suggested as one of the cellular targets for this compound. As the therapeutic use of diethyldithiocarbamate-copper complex (CuET) is expected to increase, it is of great interest to know whether this compound may be the source of drug-drug interactions via the induction of biotransformation enzymes, especially cytochromes P450 (CYPs). To this purpose, we examined the effect of CuET and compared it with typical inducers (rifampicin and dioxin) of CYPs and with well-established proteasome inhibitors (MG132 and bortezomib). Diethyldithiocarbamate-copper complex revealed inconsistent and rather modulatory effect on the expression of CYP1A2 and CYP3A4 in several cultures of human hepatocytes. Moreover, it was able to cause neither ubiquitin accumulation nor significant and dose-dependent inhibition of proteasome activity. It had no effect on essential transcription factors involved in regulation of selected CYPs, aryl hydrocarbon (AhR) nor pregnane X receptor (PXR). However, the AhR protein was increased in majority of examined hepatocyte cultures. The main finding of this study is that: (i) disulfiram-copper complex is not the cause of drug-drug interactions via CYP1A2/3A4 induction; (ii) proteasome inhibitors may have different impact on studied parameters in given in vitro system.

• Klíčová slova
• Antabuse, CYP2E1, CYP3A4, bortezomib, disulfiram, human hepatocytes, pregnane X receptor,
• MeSH
• cytochrom P-450 CYP1A2 metabolismus   MeSH
• cytochrom P-450 CYP3A metabolismus   MeSH
• dithiokarb farmakologie   MeSH
• dospělí MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• inhibitory proteasomu farmakologie   MeSH
• kultivované buňky MeSH
• lékové interakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• měď farmakologie   MeSH
• pregnanový X receptor MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• senioři MeSH
• steroidní receptory metabolismus   MeSH
• transkripční faktory metabolismus   MeSH
• uhlovodíky metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CYP1A2 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A2 MeSH
• cytochrom P-450 CYP3A MeSH
• dithiokarb MeSH
• inhibitory proteasomu MeSH
• měď MeSH
• pregnanový X receptor MeSH
• proteasomový endopeptidasový komplex MeSH
• steroidní receptory MeSH
• transkripční faktory MeSH
• uhlovodíky MeSH

The term compound receptors (C.R.) is used here to describe reversible molecular complexes in the cell membrane which attain their final biologically active structure by rearrangement and assembly of several structural subunits. The C.R. to be discussed involve the participation of the glycoproteins belonging to the major histocompatibility complex (MHC), notably of class I molecules which are themselves reversible compounds of a heavy chain and a light chain (beta 2-m). The main thesis of this discussion is the postulate that the fundamental immunological phenomenon known as MHC restriction is due to the formation in the membrane of reversible C.R. with additional roles in the physiology of the cell. The interaction between MHC class I molecules and insulin receptor molecules will be mentioned as an illustration of the general hypothesis.

• MeSH
• bezobratlí genetika   imunologie   MeSH
• biologická evoluce MeSH
• buněčná membrána imunologie   fyziologie   MeSH
• hlavní histokompatibilní komplex * MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• receptor inzulinu fyziologie   MeSH
• receptory buněčného povrchu fyziologie   MeSH
• T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• receptor inzulinu MeSH
• receptory buněčného povrchu MeSH

AIMS: Haloperidol is an antipsychotic agent and acts as dopamine D2 receptor (D2R) antagonist, as a prototypical ligand of sigma1 receptors (Sig1R) and it increases expression of type 1 IP3 receptors (IP3R1). However, precise mechanism of haloperidol action on cardiomyocytes through dopaminergic signaling was not described yet. This study investigated a role of dopamine receptors in haloperidol-induced increase in IP3R1 and Sig1R, and compared physiological effect of melperone and haloperidol on basic heart parameters in rats. MATERIALS AND METHODS: We used differentiated NG-108 cells and H9c2 cells. Gene expression, Western blot and immunofluorescence were used to evaluate haloperidol-induced differences; proximity ligation assay (PLA) and immunoprecipitation to determine interactions of D1/D2 receptors. To evaluate cardiac parameters, Wistar albino male rats were used. KEY FINDINGS: We have shown that antagonism of D2R with either haloperidol or melperone results in upregulation of both, IP3R1 and Sig1R, which is associated with increased D2R, but reduced D1R expression. Immunofluorescence, immunoprecipitation and PLA support formation of heteromeric D1/D2 complexes in H9c2 cells. Treatment with haloperidol (but not melperone) caused decrease in systolic and diastolic blood pressure and significant increase in heart rate. SIGNIFICANCE: Because D1R/D2R complexes can engage Gq-like signaling in other experimental systems, these results are consistent with the possibility that disruption of D1R/D2R complex in H9c2 cells might cause a decrease in IP3R1 activity, which in turn may account for the increase expression of IP3R and Sig1R. D2R is probably not responsible for changes in cardiac parameters, since melperone did not have any effect.

• Klíčová slova
• D1R/D2R heterodimeric complex, Dopamine D2 receptor, H9c2 cell line, Haloperidol,
• MeSH
• antagonisté dopaminu D2 farmakologie   MeSH
• antagonisté dopaminu farmakologie   MeSH
• buněčné linie MeSH
• haloperidol farmakologie   MeSH
• potkani Wistar MeSH
• receptory dopaminu D1 genetika   metabolismus   MeSH
• receptory dopaminu D2 genetika   metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• srdce účinky léků   MeSH
• srdeční frekvence účinky léků   MeSH
• vazba proteinů účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antagonisté dopaminu D2 MeSH
• antagonisté dopaminu MeSH
• haloperidol MeSH
• receptory dopaminu D1 MeSH
• receptory dopaminu D2 MeSH

The immunogenome is the part of the genome that underlies immune mechanisms and evolves under various selective pressures. Two complex regions of the immunogenome, major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes, play an important role in the response to selective pressures of pathogens. Their importance is expressed by their genetic polymorphism at the molecular level, and their diversity associated with different types of diseases at the population level. Findings of associations between specific combinations of MHC/NKR haplotypes with different diseases in model species suggest that these gene complexes did not evolve independently. No such associations have been described in horses so far. The aim of the study was to detect associations between MHC and NKR gene/microsatellite haplotypes in three horse breed groups (Camargue, African, and Romanian) by statistical methods; chi-square test, Fisher's exact test, Pearson's goodness-of-fit test and logistic regression. Associations were detected for both MHC/NKR genes and microsatellites; the most significant associations were found between the most variable KLRA3 gene and the EQCA-1 or EQCA-2 genes. This finding supports the assumption that the KLRA3 is an important receptor for MHC I and that interactions of these molecules play important roles in the horse immunity and reproduction. Despite some limitations of the study such as low numbers of horses or lack of knowledge of the selected genes functions, the results were consistent across different statistical methods and remained significant even after overconservative Bonferroni corrections. We therefore consider them biologically plausible.

• Klíčová slova
• MHC genes, NKR genes, horse, immunogenome,
• MeSH
• alely MeSH
• chov MeSH
• hlavní histokompatibilní komplex * genetika   MeSH
• koně genetika   MeSH
• lidé MeSH
• polymorfismus genetický * MeSH
• receptory buněk NK genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory buněk NK MeSH

The lipoglycoproteins of the mammalian WNT family induce β-catenin-dependent signaling through interaction with members of the Class Frizzled receptors and LDL receptor-related protein 5/6 (LRP5/6) albeit with unknown selectivity. The 10 mammalian Frizzleds (FZDs) are seven transmembrane (7TM) spanning receptors and have recently been classified as G protein-coupled receptors (GPCRs). This review summarizes the current knowledge about WNT/FZD selectivity and functional selectivity, the role of co-receptors for signal specification, the formation of receptor complexes as well as the kinetics and mechanisms of signal initiation with focus on WNT/β-catenin signaling. In order to exploit the true therapeutic potential of WNT/FZD signaling to treat human disease, it is clear that substantial progress in the understanding of receptor complex formation and signal specification has to precede a mechanism-based drug design targeting WNT receptors.

• Klíčová slova
• Canonical signaling, Class Frizzled, GPCR, LRP5/6, Receptor complex,
• MeSH
• frizzled receptory chemie   metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• ligandy MeSH
• multimerizace proteinu MeSH
• signální dráha Wnt * MeSH
• substrátová specifita MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• frizzled receptory MeSH
• ligandy MeSH

The exposure of a DNA-protein regulatory complex to ionising radiation induces damage to both partner biomolecules and thus can affect its functioning. Our study focuses on a complex formed by the estrogen response element (ERE) DNA and the recombinant human estrogen receptor alpha (ER), which mediates the signalling of female sex hormones, estrogens. The method of native polyacrylamide retardation gel electrophoresis is used to study the stability of the complex under irradiation by low LET radiation ((60)Co gamma rays) and the ability of the separately irradiated partners to form complexes. The relative probabilities of ERE DNA strand breakage and base damages as well as the probabilities of damages to the ER binding domain are calculated using the Monte Carlo method-based model RADACK.

• MeSH
• alfa receptor estrogenů chemie   účinky záření   ultrastruktura   MeSH
• chemické modely MeSH
• dávka záření MeSH
• DNA vazebné proteiny chemie   účinky záření   MeSH
• DNA chemie   účinky záření   MeSH
• estrogeny chemie   účinky záření   MeSH
• lidé MeSH
• molekulární modely MeSH
• počítačová simulace MeSH
• poškození DNA * MeSH
• responzivní elementy účinky záření   MeSH
• vztah dávky záření a odpovědi MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alfa receptor estrogenů MeSH
• DNA vazebné proteiny MeSH
• DNA MeSH
• estrogeny MeSH

Receptor tyrosine kinases (RTKs) form multiprotein complexes that initiate and propagate intracellular signals and determine the RTK-specific signalling patterns. Unravelling the full complexity of protein interactions within the RTK-associated complexes is essential for understanding of RTK functions, yet it remains an understudied area of cell biology. We describe a comprehensive approach to characterize RTK interactome. A single tag immunoprecipitation and phosphotyrosine protein isolation followed by mass-spectrometry was used to identify proteins interacting with fibroblast growth factor receptor 3 (FGFR3). A total of 32 experiments were carried out in two different cell types and identified 66 proteins out of which only 20 (30.3%) proteins were already known FGFR interactors. Using co-immunoprecipitations, we validated FGFR3 interaction with adapter protein STAM1, transcriptional regulator SHOX2, translation elongation factor eEF1A1, serine/threonine kinases ICK, MAK and CCRK, and inositol phosphatase SHIP2. We show that unappreciated signalling mediators exist for well-studied RTKs, such as FGFR3, and may be identified via proteomic approaches described here. These approaches are easily adaptable to other RTKs, enabling identification of novel signalling mediators for majority of the known human RTKs.

• Klíčová slova
• FGFR3, Fibroblast growth factor, interactome, receptor tyrosine kinase, signal transduction,
• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• buňky NIH 3T3 MeSH
• cyklin-dependentní kinasy genetika   metabolismus   MeSH
• elongační faktor 1 genetika   metabolismus   MeSH
• endozomální třídící komplexy pro transport genetika   metabolismus   MeSH
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy genetika   metabolismus   MeSH
• fosfoproteiny genetika   metabolismus   MeSH
• fosforylace MeSH
• HEK293 buňky MeSH
• homeodoménové proteiny genetika   metabolismus   MeSH
• kinasa aktivující cyklin dependentní kinasy MeSH
• lidé MeSH
• mapování interakce mezi proteiny MeSH
• myši MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• proteomika metody   MeSH
• receptor fibroblastových růstových faktorů, typ 3 genetika   metabolismus   MeSH
• regulace genové exprese * MeSH
• signální transdukce genetika   MeSH
• stanovení celkové genové exprese MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• CILK1 protein, human MeSH Prohlížeč
• cyklin-dependentní kinasy MeSH
• EEF1A1 protein, human MeSH Prohlížeč
• elongační faktor 1 MeSH
• endozomální třídící komplexy pro transport MeSH
• FGFR3 protein, human MeSH Prohlížeč
• fosfatidylinositol-3,4,5-trisfosfát-5-fosfatasy MeSH
• fosfoproteiny MeSH
• homeodoménové proteiny MeSH
• INPPL1 protein, human MeSH Prohlížeč
• kinasa aktivující cyklin dependentní kinasy MeSH
• MAK protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• SHOX2 protein, human MeSH Prohlížeč
• STAM protein, human MeSH Prohlížeč