Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bicuculline-insensitive receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), GABAB receptors, are a distinct subclass of receptors that mediate depression of synaptic transmission and contribute to neuronal inhibition. When activated, these receptors reduce transmission at excitatory and inhibitory synapses, as a result of an increase in K+ conductance, or a decrease in voltage-dependent Ca2+ currents. They are also linked to G-proteins, or intracellular effector systems in a very complex manner. The recent development of highly specific and potent agonists and antagonists for these receptors has led to a much better understanding of their physiology and pharmacology, including their heterogeneity, as well as their molecular biology. Over the past year, expression and cloning studies have contributed to major advances in characterizing GABAB receptor structure, with the discovery of the amino acid sequences of GABABR1a/R1b splice variants and GABABR2 receptors. These isoforms are widely distributed throughout the nervous system, and can be functionally expressed. Importantly, GABABR2 receptors can form a heteromeric assembly with GABABR1 proteins to operate as a heterodimer that displays robust coupling to inward-rectifying K+ channels, as well as inhibition of forskolin-stimulated adenylate cyclase activity. Further insights underlying the mechanisms of GABAB receptor functions can now be gained, leading ultimately to the therapeutic potential of drugs acting at these sites. It is increasingly clear that new information on GABAB receptor molecular structure will provide a plethora of targets for pharmaceutical intervention in areas such as drug addiction, nociception and absence seizures. This review summarizes the renewed efforts, and highlights the recent advances emerging in this field.
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PMID:Recent advances in GABAB receptors: from pharmacology to molecular biology. 1126 57

gamma-Aminobutyric acid B (GABA(B)) receptor is the first discovered G protein-coupled receptor that requires two subunits, GB1 and GB2, to form a functional receptor. Whereas the molecular and functional characteristics of GABA(B) receptors have been recently extensively studied, the mechanisms underlying receptor desensitization and endocytosis are still poorly understood. We have investigated the effect of continuous agonist exposure on the human GABA(B) receptor functional response and redistribution when expressed in Chinese hamster ovary (CHO-K1) cells. The wild-type GABA(B) receptor-mediated inhibition of the adenylate cyclase activity appeared desensitized after 2 h in the presence of GABA (100 microM). Fusion proteins were generated by attachment of cyan fluorescent protein (CFP) and yellow fluorescent protein (YFP) to GB1 and GB2, respectively, and confocal microscopy experiments in intact living cells semi-stably expressing the constructs were performed. Incubation of co-expressing CFP-GB1 and YFP-GB2 cells in the presence of GABA (100 microM) for 2 h induced a profound receptor internalization, and CFP-GB1 and YFP-GB2 appeared co-localized in the endosome (labelled with Cy3-transferrin). The internalization was blocked by a selective GABA(B) receptor antagonist. These results represent the first clear visualization of agonist-induced internalization of the unique heterodimeric GABA(B) receptor.
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PMID:Agonist-induced desensitization and endocytosis of heterodimeric GABAB receptors in CHO-K1 cells. 1463 70

Previous studies have demonstrated that the gamma-aminobutyric acid type B (GABA(B)) receptor plays an essential role in modulating neurotransmitter release and regulating the activity of ion channels and adenyl cyclase. However, whether the naturally occurring polymorphisms in the two GABA(B) receptor subunit genes interact with each other to alter susceptibility to nicotine dependence (ND) remains largely unknown. In this study, we genotyped 5 and 33 single nucleotide polymorphisms (SNPs) for GABA(B) receptor subunit 1 and 2 genes (GABBR1, GABBR2), respectively, in a sample of 2037 individuals from 602 nuclear families of African- American (AA) or European-American (EA) origin. We conducted association analyses to determine (1) the association of each subunit gene with ND at both the individual SNP and haplotype levels and (2) the collective effect(s) of SNPs in both GABA(B) subunits on the development of ND. Several individual SNPs and haplotypes in GABBR2 were significantly associated with ND in both ethnic samples. Two haplotypes in AAs and one haplotype in EAs showed a protective effect against ND, whilst two other haplotypes in AAs and three haplotypes in EAs showed a risk effect for developing ND. Interestingly, these significant haplotypes were confined to two regions of GABBR2 in the AA and EA samples. Additionally, we found two minor haplotypes in GABBR1 to be positively associated with Heaviness of Smoking Index (HSI) in the EA sample. Finally, we demonstrated the presence of epistasis between GABBR1 and GABBR2 for developing ND. The variants of GABBR1 and GABBR2 are significantly associated with ND, and the involvement of GABBR1 is most likely through its interaction with GABBR2, whereas GABBR2 polymorphisms directly alter susceptibility to ND. Future studies are needed with more dense SNP coverage of GABBR1 and GABBR2 to verify the epistatic effects of the two subunit genes.
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PMID:Association and interaction analyses of GABBR1 and GABBR2 with nicotine dependence in European- and African-American populations. 1976 58