Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite numerous studies on extrastriatal regions involved in schizophrenia, studies on the functional implications of dopamine (DA) D2 receptors in the extrastriatal regions, including the cortex and thalamus, are limited. We review postmortem and in vivo human imaging studies as well as animal studies, focusing on the function of extrastriatal DA D2 receptors and their role in the pathophysiology of schizophrenia. Based on recent findings, cortical DA D2 receptors may interact with the gamma-aminobutyric acid system to modulate DA transmission, and thalamic DA D2 receptors are likely to participate in sensory gating function into the prefrontal cortex. We have found decreased DA D2 receptors in the anterior cingulate cortex and thalamic subregions of patients with schizophrenia. These observations may suggest that alterations of extrastriatal DA D2 receptors are involved in dysregulation of DA transmission and sensory signals from the thalamus to the cortex. Excessive excitatory signals from the thalamus might flow into the cortical neurotransmission system, aggravating dysregulation of DA transmission in both the striatal and extrastriatal regions in schizophrenia. These notions suggest the need for future investigations of extrastriatal DA D2 receptor function to gain important clues regarding the pathogenesis and of possible treatments for schizophrenia.
 ...
PMID:The role of extrastriatal dopamine D2 receptors in schizophrenia. 1668 69

We have compiled significant linkage results from 20 genome scans for the autism syndrome disorder (ASD) and 2 for catatonia in schizophrenia (SZ). Localization of the markers has been updated across the studies using the same cytological (Genetic Location Database), physical (National Center for Biological Information), and genetic (Marshfield) maps. Eight autosomal chromosomes (1, 2, 3, 7, 9, 13, 15, and 17) showed significant linkages with ASD, and one with catatonia (15). Chromosome 15 was further characterized for SZ genome scans (N = 4) since catatonia was observed in SZ patients, for candidate genes for ASD and catatonia, and for the numerous chromosomal rearrangement and abnormalities associated to ASD. From these results, we observed that four potential susceptibility regions for ASD could be observed on chromosome 15 at 15q11-q13, 15q14-q21, 15q22-q23, and 15q26, respectively. All the four regions were shared between ASD and SZ, with 15q15-q21 being also shared with catatonia. Strong candidate genes, such as gamma-aminobutyric acid receptor B3, A5, and G3, have shown associations with ASD at 15q11-q13 susceptibility region where the majority of the chromosomal rearrangements are also found. On the other hand, negative association results were observed at 15q14-q21 susceptibility region for catatonia with the genes encoding the zinc transporter SLC30A4, the cholinergic receptor nicotinic alpha polypeptide 7, and the delta-like 4 Drosophila. Further, fine mapping and candidate gene analyses are needed to highlight potential common genes between ASD and catatonia for this chromosome.
 ...
PMID:Shared susceptibility region on chromosome 15 between autism and catatonia. 1669 97

Endogenous methylarginines, the catabolism products of proteins containing post-translationally methylated arginine residues, are the modulators of arginine metabolism. Endogenous methylarginines compete with arginine about cationic aminoacid transporter and some of them, e.g. asymmetric dimethylarginine (ADMA) and N-mono-methylarginine (MMA), are competitive inhibitors of nitric oxide synthases. The changes of arginine metabolism, induced by these methylarginines, may have serious consequences, because arginine is the precursor of cell-signalling molecules such as NO, agmatine, glutamate and gamma-aminobutyric acid (GABA) and the regulatory molecules polyamines. ADMA has also prooxidant properties and increases endothelial adhesiveness for monocytes. Asymmetric methyl-arginines induce endothelial dysfunction, which may be reversed by L-arginine supplementation, what is defined as "arginine paradox". The increased plasma concentration of asymmetric methylarginines is induced by hypercholesterolemic or hyperhomocysteinemic diets and by rich sodium chloride intake. The high level of plasma asymmetric methyl-arginines accompanies atherosclerosis, hypertension, chronic renal failure, diabetes, insulin resistence, hyperthyreosis, schizophrenia and sclerosis multiplex. The causes of increased concentration ADMA and MMA in these diseases are just now discovered. The hope in the future is the modulation of methylarginines concentration by regulation of expression and activities of enzymes taking part in the metabolism of these substances, particularly of dimethyl-arginine dimethyl-aminotransferase. The main aim of the present study is to pay attention to possibility of the modulation of asymmetric methyl-arginines concentration, what may be a new way of synthase nitric oxide activity regulation in vivo and may be useful in future therapy of patologies in which synthesis of NO is troubled.
 ...
PMID:[The importance of regulation of endogenous methylarginine concentrations in clinical practice]. 1678 81

Because of its control of spike-timing and oscillatory network activity, gamma-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABA(A) receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing alpha(1)GABA(A) receptors have been found to mediate sedation, whereas those expressing alpha(2)GABA(A) receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic alpha(5)GABA(A) receptors. In addition, neurons expressing alpha(3)GABA(A) receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with alpha(1)GABA(A) receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA(A) receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.
 ...
PMID:GABA(A) receptor diversity and pharmacology. 1693 11

Currently, no drugs exist that effectively treat cognition in people with schizophrenia. What is known about the neurobiology of cognition in schizophrenia is derived from the animal literature; it is inadequate and superficial. Despite this lack, pharmacologic research into potential molecular targets has uncovered several viable possibilities from animal studies. A subcommittee of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program investigated the range of putative molecular targets for treating cognition. Those targets that show promise for pharmacologic focus include the dopamine receptors (especially D1) in the prefrontal cortex (PFC), the serotonin receptors in the PFC and anterior cingulate cortex, the glutamatergic excitatory synapse, the acetylcholine nicotinic receptors in the hippocampus, the acetylcholine muscarinic receptors, and the brain gamma-aminobutyric acid (GABA) system. Once developed and tested, the effective compounds will be valuable for the treatment of the symptom domains of cognitive dysfunction and negative symptoms.
 ...
PMID:The neurobiology of cognition in schizophrenia. 1696 83

Single nucleotide polymorphisms in type A gamma-aminobutyric acid (GABA(A)) receptor beta2 subunit gene (GABRB2) were found to be associated with schizophrenia in Chinese, German, Japanese and Portuguese. To explore potential functional consequences of these DNA sequence polymorphisms, this study examined the expression and electrophysiological properties of two alternatively spliced products of GABRB2 along with genotypical disease association analysis. Real-time quantitative polymerase chain reaction, performed with a cohort of 31 schizophrenics and 31 controls of US population, showed 21.7% reduction in the expression of the long isoform beta(2L), 13.4% in the short isoform beta(2S) and 15.8% in the sum of the two isoforms beta(2T) in postmortem schizophrenic brain. Furthermore, two independent mRNA quantitation methods showed that the relative expression of the long over the short isoforms was significantly decreased, suggesting the occurrence of altered splicing, in schizophrenia. In male schizophrenics, the heterozygous genotypes of rs1876071 (T/C) and rs1876072 (A/G) were correlated with reduced expression of beta(2L), beta(2S) and beta(2T), and the heterozygous of rs2546620 (A/G) and homozygous-minor of rs1876071 (C/C) and rs1876072 (G/G) were correlated with reduced expression of beta(2T). Significant correlations of expression levels with different alleles and haplotypes were also indicated by quantitative trait analysis. Recombinant GABA(A) receptors expressed in HEK293 human cells containing beta(2L) underwent a steeper current rundown upon repetitive GABA activation than receptors containing beta(2S). The results thus revealed genotype-dependent expression of the alternatively spliced isoforms of GABA(A) receptor beta2 subunit, giving rise to electrophysiological consequences that could play an important role in the pathogenesis mechanism of schizophrenia.
 ...
PMID:Two isoforms of GABA(A) receptor beta2 subunit with different electrophysiological properties: Differential expression and genotypical correlations in schizophrenia. 1698 89

We performed a whole genome microsatellite marker scan in six multiplex families with bipolar (BP) mood disorder ascertained in Antioquia, a historically isolated population from North West Colombia. These families were characterized clinically using the approach employed in independent ongoing studies of BP in the closely related population of the Central Valley of Costa Rica. The most consistent linkage results from parametric and non-parametric analyses of the Colombian scan involved markers on 5q31-33, a region implicated by the previous studies of BP in Costa Rica. Because of these concordant results, a follow-up study with additional markers was undertaken in an expanded set of Colombian and Costa Rican families; this provided a genome-wide significant evidence of linkage of BPI to a candidate region of approximately 10 cM in 5q31-33 (maximum non-parametric linkage score=4.395, P<0.00004). Interestingly, this region has been implicated in several previous genetic studies of schizophrenia and psychosis, including disease association with variants of the enthoprotin and gamma-aminobutyric acid receptor genes.
 ...
PMID:Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31-34. 1698 60

Impairments in certain cognitive functions mediated by the dorsolateral prefrontal cortex, such as working memory, are core features of schizophrenia. Convergent findings suggest that these disturbances are associated with alterations in markers of inhibitory gamma-aminobutyric acid and excitatory glutamate neurotransmission in the dorsolateral prefrontal cortex. Specifically, reduced gamma-aminobutyric acid synthesis is present in the subpopulation of gamma-aminobutyric acid neurons that express the calcium-binding protein parvalbumin. Despite presynaptic and postsynaptic compensatory responses, the resulting impaired inhibitory regulation of pyramidal neurons contributes to a reduction in the synchronized neuronal activity that is required for working memory function. Several lines of evidence suggest that these changes may be either secondary to or exacerbated by impaired signaling via the N-methyl-d-aspartate class of glutamate receptors. These findings suggest specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
 ...
PMID:Cognitive dysfunction in schizophrenia: convergence of gamma-aminobutyric acid and glutamate alterations. 1703 Jun 51

The alpha1/beta2/gamma2-containing heteropentamer is the most abundant gamma-amino-n-butyric acid type A receptor subtype in mammalian brains and the corresponding genes, the GABRA1, GABRB2, and GABRG2 genes, are located in chromosomal region 5q34 that several genome wide scans have implicated as a susceptibility region for schizophrenia. Given this positional and functional evidence, Lo et al. (Mol Psychiatry 2004; 9: 603-608) performed systematic linkage disequilibrium mapping of the GABAAR gene cluster on 5q34 in 130 schizophrenic patients and 170 controls, all of Chinese Han origin. In the single locus and haplotype analyses, single nucleotide polymorphisms in the GABRB2 gene showed highly significant association. The estimated effect caused by GABRB2 varied between odds ratios of 2.27 and 5.12. In order to re-examine their findings, we analyzed the most significantly associated single nucleotide polymorphism in the GABRB2 gene in a sample of 367 patients with schizophrenia and 360 controls, all of German descent. Our sample had a sufficient power to detect the effects described. Neither single marker nor haplotype analysis revealed a significant association with the disease status. Thus, our results do not support the hypothesis that genetic variation at the GABRB2 locus plays a major role in schizophrenic patients of European descent and that such variation would explain the previously observed linkage findings at this chromosomal region.
 ...
PMID:No evidence for an association between variants at the gamma-amino-n-butyric acid type A receptor beta2 locus and schizophrenia. 1716 45

Fast synaptic inhibition in the brain and spinal cord is mediated largely by ionotropic gamma-aminobutyric acid (GABA) receptors. GABAA receptors play a key role in controlling neuronal activity; thus modulating their function will have important consequences for neuronal excitation. GABAA receptors are important therapeutic targets for a range of sedative, anxiolytic, and hypnotic agents and are involved in a number of CNS diseases, including sleep disturbances, anxiety, premenstrual syndrome, alcoholism, muscle spasms, Alzheimer's disease, chronic pain, schizophrenia, bipolar affective disorders, and epilepsy. This review focuses on the functional and pharmacological properties of GABAA receptors and trafficking as an essential mechanism underlying the dynamic regulation of synaptic strength.
 ...
PMID:GABAA receptors: properties and trafficking. 1736 82


<< Previous 1 2 3 4 5 6 7 8 9 10