Cloning and sequencing techniques now allow us to characterize genes directly instead of having to deduce their properties from their effects. This new genetics reaches its apotheosis in the plan to obtain the complete DNA sequence of the human genome, but this is far beyond the capacity of present sequencing methods. Small 'model' genomes, 'such as those of Escherichia coli (4.7 megabases (Mb) and yeast (14 Mb), or even those of Caenorhabditis elegans (100 Mb) and Drosophila (165 Mb), are better scaled to existing technology. The yeast genome will contain genes with functions common to all eukaryotic cells, and those of simple multicellular organisms may throw light on the genetic specification of more complex functions. However, vertebrates differ in their morphology and development, so the ideal model would be a vertebrate genome of minimum size and complexity but with maximum homology to the human genome. Here we report the characterization of the small genome (400 Mb) of the tetraodontoid fish, Fugu rubripes. A random sequencing approach supported by gene probing shows that the haploid genome contains 400 Mb of DNA, of which more that 90% is unique. This genome is 7.5 times smaller than the human genome and because it has a similar gene repertoire it is the best model genome for the discovery of human genes.
Brain dopaminergic transmission is a critical component in numerous vital functions, and its dysfunction is involved in several disorders, including addiction and Parkinson's disease. Responses to dopamine are mediated via G protein-coupled dopamine receptors (D1-D5). Desensitization of G protein-coupled receptors is mediated via phosphorylation by members of the family of G protein-coupled receptor kinases (GRK1-GRK7). Here we show that GRK6-deficient mice are supersensitive to the locomotor-stimulating effect of psychostimulants, including cocaine and amphetamine. In addition, these mice demonstrate an enhanced coupling of striatal D2-like dopamine receptors to G proteins and augmented locomotor response to direct dopamine agonists both in intact and in dopamine-depleted animals. The present study indicates that postsynaptic D2-like dopamine receptors are physiological targets for GRK6 and suggests that this regulatory mechanism contributes to central dopaminergic supersensitivity.
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