Tourette's syndrome and homozygosity for the dopamine D3 receptor gene. German Tourette's Syndrome Collaborative Research Group.
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Homozygote↗
Biomedical subjects
J Hebebrand
Publications and source records attributed to J Hebebrand.
A putaminal lesion in an adolescent with obsessive-compulsive disorder and atypical anorexia nervosa.
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Adolescent↗
[Genetics of reading-spelling difficulties].
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Adolescent↗
A critical analysis of data presented in eight studies favouring X-linkage of bipolar illness with special emphasis on formal genetic aspects.
High lod scores were obtained in several X-linkage studies of bipolar illness under the assumption that a subgroup of manic depression follows an X-linked dominant mode of inheritance. We have previously shown that the segregation patterns do not substantiate this assumption. We now statistically address the lack of evidence for X-linked inheritance by sex-dependently analyzing segregation ratios and clinical data presented in eight positive X-linkage studies. Accordingly, affected males have significantly fewer offspring, a lower mean age and a higher bipolar to unipolar ratio than affected females. There are two possible explanations for these findings: either the X-linked subgroup of bipolar illness has unique features that have not been accounted for clinically, or (more probably) the pedigree structures could also (and might be more likely to) result from ascertaining kindreds following autosomal or multifactorial inheritance only, with exclusion of kindreds encompassing male to male transmission.
Adult↗
A critical appraisal of X-linked bipolar illness. Evidence for the assumed mode of inheritance is lacking.
The major assumption underlying all X-linkage studies of bipolar disorder has been that a subgroup of manic-depressive illness follows an X-linked dominant mode of inheritance. An evaluation of the segregation patterns in the pedigrees that have been analysed for X-linkage over the past 20 years does not support this assumption, because the formal genetic criteria for an X-linked dominant mode of inheritance are virtually absent. Not a single pedigree has been ascertained in which the segregation pattern is suggestive of the assumed mode of inheritance. This is mainly because segregation ratios characteristic for X-linked dominant inheritance cannot be observed among the offspring of affected males.
Bipolar Disorder↗
Interaction of beta-carboline with chick embryo spontaneous motility.
The effect of beta-carboline (beta-CCE) on spontaneous motility and its development was studied in chick embryos between the 11th and 19th day of incubation. 1. Acutely administered beta-CCE (7.5 mg/kg e.w.) already induced significant activation of motility in 11-day-old embryos. From the 17th day of incubation activation acquired a paroxysmal character. 2. In spinal embryos (decapitated on the second day of incubation) there was no such activating effect, demonstrating that it is associated with supraspinal components of the CNS. 3. In chronic administration from the fourth day of incubation (1.55 +/- 0.24 mg/kg e.w./24h), beta-CCE led to reduced development of spontaneous motility. The effect was concentrated in the period between the fourth and eighth day of incubation. The chronic administration of beta-CCE augmented the activating effect of metrazol and weakened GABA-inhibition of spontaneous motility. 4. On the basis of their findings, the authors express the hypothesis that the benzodiazepine beta-CCE-sensitive component of the complex GABA receptor evidently already functions from the beginning of the second half of incubation of chick embryos.
Animals↗
[Significant progress in the genetic origin of Martin-Bell syndrome including diagnostic consequences].
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Abnormalities, Multiple↗
Kindling does not induce persistent changes in fluorographic labeling patterns of benzodiazepine binding proteins in various rat brain regions.
The GABAA receptor has been implicated in the mechanisms underlying the phenomenon of kindling. Photoaffinity labeling with 3H-flunitrazepam followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis allows the fluorographic visualization of GABAA receptor proteins with benzodiazepine binding sites which presumably correspond to different alpha-subtypes. This method offers an opportunity to investigate whether up- or down-regulation of single benzodiazepine binding proteins occurs. In the present study, labeling patterns of benzodiazepine binding proteins were determined in 12 brains regions of amygdala-kindled rats (2 weeks after the last fully kindled seizure) and sham-operated controls. For most brain regions, labeling patterns were separately determined for the ipsi- and contralateral side. A comparison of the labeling patterns thus obtained revealed no persistent changes between kindled animals and controls in any of the brain regions, including amygdala, substantia nigra and hippocampus. Thus, we conclude that kindling does not induce fluorographically detectable changes in the expression patterns of the benzodiazepine binding proteins. The results confirm the existence of regional heterogeneity of benzodiazepine binding proteins and extend the findings to brain regions which had previously not been investigated.
Affinity Labels↗
Ontogeny of the benzodiazepine receptor in human brain: fluorographic, immunochemical, and reversible binding studies.
The prenatal and postnatal human ontogeny of the central benzodiazepine receptor was investigated in six different brain regions between week 24 postconception and age 14 years. Binding studies, which were performed with [3H]flunitrazepam [( 3H]FNZ), revealed a steep increase in receptor density postnatally in frontal cortex and cerebellum. Bmax values were higher in medulla oblongata, pons, and thalamus than in cortex and cerebellum up to week 26. After that, receptor densities declined significantly in medulla and olive. The same tendency was apparent in pons, whereas receptor density remained unchanged in thalamus. The early ontogeny of the benzodiazepine receptor was also evaluated in fluorographs [( 3H]FNZ) and immunoblots using the alpha 1-subunit-specific monoclonal antibody (mAb) bd-24. Specific radiolabeled proteins with molecular weights of 53K and 59K were visible in cortical membranes from gestational week 8, the earliest time investigated. During further development, the intensity of the 53K band increased without changes in the 59K band. As in other species, postmortem proteolysis in human brain led to a specifically labeled peptide of 47K. The mAb bd-24 immunolabeled only the 53K protein and the 47K peptide.
Adolescent↗
Calpain inhibitor I prevents rapid postmortem degradation of benzodiazepine binding proteins: fluorographic and immunological evidence.
Endogenous proteolysis of the major central benzodiazepine (BZ) binding protein of 53K occurs rapidly postmortem and leads to a fragment of 47K. To determine indirectly the protease responsible for this proteolysis, membranes of porcine cortex were prepared from homogenates, which were either frozen immediately or left at room temperature for 12 h in the presence or absence of various representative protease inhibitors. Membranes were subsequently photolabeled with [3H]flunitrazepam, and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography or immunoblotted using an alpha-subunit-specific monoclonal antibody bd-24. Both fluorographs and immunoblots revealed that calpain inhibitor I, Ep-459 (E-64 analogue), and EDTA (greater than or equal to 1 mM) prevent endogenous proteolysis. In future studies one of these inhibitors should be added to receptor preparations. The results indicate that calpain is the responsible protease.
Affinity Labels↗
Photolabeled tryptic degradation products of benzodiazepine-binding proteins are glycopeptides. Implications for localization of cleavage sites.
Crude synaptic membranes of avian and mammalian brain tissue were photolabeled with the benzodiazepine-receptor ligand [3H]flunitrazepam and subsequently treated extensively with trypsin followed by incubation with endoglycosidase F. SDS-polyacrylamide gel electrophoresis and fluorography revealed that the final tryptic degradation product of 25 kDa in both pigeon and calf brain is deglycosylated in two steps. These results were confirmed by immunoblots of similarly pretreated membranes of pig brain using the alpha-subunit-specific monoclonal antibody bd-24. Benzodiazepine-receptor binding and its enhancement by GABA are largely retained after trypsinization. Based on the proposed transmembrane topology for the alpha-subunits of the GABA/benzodiazepine receptor, we suggest that the large N-terminal domain of benzodiazepine-binding proteins is protected against tryptic cleavage.
Animals↗
Postmortem degradation alters fluorographic labeling patterns and affinities of benzodiazepine binding proteins.
To investigate the effect of endogenous proteolysis on the molecular weights of the benzodiazepine binding proteins, brains of trout, chicken, and rat were removed immediately after death and stored at room temperature for various periods of time before they were frozen. Photoaffinity labeling of membranes with [3H]flunitrazepam, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and fluorography, revealed proteolytic fragments of 47K in trout, chicken, and rat. The proteolysis set in rapidly after death. Seemingly in parallel with the degradation observed fluorographically, the affinity for [3H]flunitrazepam increased without systematic changes in receptor density. The degradation pattern was not identical to that of the photolabeled trypsinized benzodiazepine binding proteins. The endogenous proteolytic fragments were deglycosylated in two steps. In conclusion, proteolytic effects must be taken into account when interpreting labeling patterns and binding parameters.
Animals↗
A comparative phylogenetic study of the distribution of cerebellar GABAA/benzodiazepine receptors using radioligands and monoclonal antibodies.
In mammalian cerebella the distribution of high affinity GABAA and benzodiazepine binding sites does not parallel each other. Differences in the molecular structure of the receptor complex or conformational changes have been proposed to explain the lack of a co-localization of these binding sites. Using radio- and immunohistochemistry we were able to obtain similar results for cerebella of non-mammalian species, indicating that the respective distribution of the binding sites is well conserved throughout vertebrate evolution. The gamma-aminobutyric acid agonist [3H]muscimol and the beta-subunit specific antibody bd-17 strongly labeled the granular layer. The radioligands for the benzodiazepine binding site [3H]flunitrazepam and [3H]Ro 15-1788 revealed species variation in the ratio of benzodiazepine receptor density in the granular and molecular layers. In human and pig cerebellum, the localization of antigenic sites recognized by the alpha-subunit specific antibody bd-24 deviates from the distribution of the benzodiazepine binding sites.
Animals↗
Persistence of species variation and regional heterogeneity of the apparent molecular masses of benzodiazepine-binding proteins after deglycosylation.
Brain membrane preparations of different vertebrates were photoaffinity labeled with [3H]flunitrazepam and subsequently deglycosylated with endoglycosidase F and peptide N-glycopeptidase. SDS-polyacrylamide gel electrophoresis followed by fluorography revealed that each benzodiazepine-binding protein is deglycosylated in two steps, indicating that each protein has two glycosylation sites. Species variation of the apparent molecular masses of the benzodiazepine-binding proteins and regional heterogeneity in avians persist after deglycosylation. These results indicate that the alpha-subunit(s) of the GABA/benzodiazepine receptor has undergone electrophoretically detectable changes in its amino acid composition during vertebrate evolution. The existence of at least two different alpha-subunits in avians is further substantiated.
Animals↗
The shark GABA-benzodiazepine receptor: further evidence for a not so late phylogenetic appearance of the benzodiazepine receptor.
Whilst the brain-specific benzodiazepine receptor has been assumed to show a late evolutionary appearance, we present evidence for the presence of a central benzodiazepine binding site in sharks, which shows a high affinity for [3H]Ro 15-1788. However, the receptor density and the affinities of several benzodiazepine receptor ligands are lower than in mammals, thus presumably explaining why the benzodiazepine binding sites had previously escaped detection in elasmobranchs. Additionally, radio- and immunohistochemistry were performed to localize the radioligand binding sites and the antigenic sites of the shark gamma-aminobutyric acid (GABA)-benzodiazepine receptor. In cerebellum, the granular layer reveals a high density of [3H]muscimol binding sites. The immunoreaction obtained with the beta-subunit-specific monoclonal antibody bd-17 seemingly parallels the distribution of high-affinity GABA binding sites. In contrast, [3H]Ro 15-1788 binding sites are evenly distributed in the molecular and granular layers, thus the results are similar to those previously described for rat cerebellum. Apparently, the respective distributions in this brain region are well conserved throughout vertebrate evolution.
Animals↗
The concept of isoreceptors: application to the nicotinic acetylcholine receptor and the gamma-aminobutyric acidA/benzodiazepine receptor complex.
The concept of isoreceptors offers a possible clue to account for pharmacological and biochemical heterogeneity in specific receptor systems. The existence of isozymes has set the foundation for the definition of isoreceptors. The resulting criteria are applied to two central receptor complexes. Accordingly, the nicotinic acetylcholine receptor is defined as an isoreceptor, and research results on the GABA/benzodiazepine receptor are interpreted under the consideration of the possible existence of isoreceptors.
Animals↗
Early ontogeny of the central benzodiazepine receptor in human embryos and fetuses.
The early ontogeny of the central benzodiazepine receptor (BZR) was investigated in human embryos and fetuses between 7 and 26 weeks of gestation. Brain tissue was gained from terminated pregnancies or spontaneous abortions. Binding studies, which were performed with 3H-flunitrazepam (FNZ), revealed that specific benzodiazepine binding is already detectable at an embryonal age of 7 weeks post conceptionem. Binding at this early stage can be displaced potently by clonazepam and the inverse agonist beta-CCE. Additionally, 3H-FNZ binding is enhanced by GABA. Thus, benzodiazepine binding is of the central type. Receptor density increases steeply in whole brain between weeks 8 and 11 of gestation. In frontal cortex receptor density increases gradually between weeks 12 and 26 of gestation. No specific fetal disease entity (including trisomy 21) was consistently associated with exceptionally high or low Bmax-values.
Brain↗
Phylogenetic conservation of the benzodiazepine binding sites: pharmacological evidence.
Phylogenetic research can help to elucidate the structure of the GABA/benzodiazepine receptor complex. In this study the evolution of the beta-carboline binding site was traced to see whether it paralleled that of the benzodiazepine binding site. The ratio of [3H]ethyl-beta-carboline-3-carboxylate (beta-CCE) to [3H]flunitrazepam (FNZ) binding sites was determined in several nonmammalian species. The results further substantiate the tight link between these two binding sites. Photoaffinity labelling of the benzodiazepine receptor (BZR) has revealed phylogenetic variation of the molecular weight of the benzodiazepine binding proteins. The IC50 values for inhibition of [3H]FNZ by various compounds which are active at the central benzodiazepine receptors were determined in three phylogenetically distant species that each showed distinct subunit patterns. In these species, the respective affinities of the compounds were remarkably similar, suggesting that the binding sites for benzodiazepines are conserved in higher bony fishes and tetrapods. The conserved binding sites, in addition to recent immunological results obtained in other research groups, provide further evidence for the existence of the GABA/BZR as an isoreceptor complex.
Affinity Labels↗