PubMed · 7379
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K G Beam, P Greengard. 1976. Cyclic nucleotides, protein phosphorylation and synaptic function.. https://doi.org/10.1101/sqb.1976.040.01.017
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Rapid expansion of available data, both phenotypic and genotypic, for multiple strains of mice has enabled the development of new methods to interrogate the mouse genome for functional genetic perturbations. In silico mapping provides an expedient way to associate the natural diversity of phenotypic traits with ancestrally inherited polymorphisms for the purpose of dissecting genetic traits. In mouse, the current single nucleotide polymorphism (SNP) data have lacked the density across the genome and coverage of enough strains to properly achieve this goal. To remedy this, 470,407 allele calls were produced for 10,990 evenly spaced SNP loci across 48 inbred mouse strains. Use of the SNP set with statistical models that considered unique patterns within blocks of three SNPs as an inferred haplotype could successfully map known single gene traits and a cloned quantitative trait gene. Application of this method to high-density lipoprotein and gallstone phenotypes reproduced previously characterized quantitative trait loci (QTL). The inferred haplotype data also facilitates the refinement of QTL regions such that candidate genes can be more easily identified and characterized as shown for adenylate cyclase 7.
Ethanol and other drugs of abuse modulate cAMP-PKA signaling within the mesolimbic reward pathway. To understand the role of the cAMP-PKA signal transduction in mediating the effects of ethanol, we have studied ethanol consumption and the sedative effects of ethanol in three lines of genetically modified mice. We report that mice with the targeted disruption of one Gsalpha allele as well as mice with reduced neuronal PKA activity have decreased alcohol consumption compared with their wild-type littermates. Genetic reduction of cAMP-PKA signaling also makes mice more sensitive to the sedative effects of ethanol, although plasma ethanol concentrations are unaffected. In contrast, mice with increased adenylyl cyclase activity resulting from the transgenic expression of a constitutively active form of Gsalpha in neurons within the forebrain are less sensitive to the sedative effects of ethanol. Thus, the cAMP-PKA signal transduction pathway is critical in modulating sensitivity to the sedative effects of ethanol as well as influencing alcohol consumption.
The limited information available regarding the gene structure of adenylyl cyclases (AC), which catalyze the synthesis of cAMP, suggests a complex arrangement with many exons and large introns such that molecular techniques to define these gene structures are time- and labor-intensive. We report here the use of a computer-based approach involving the assembly of fragmented sequence data generated by the Human Genome Project and nucleic acid analysis software to decipher the gene structure of human and murine AC 6 and other human AC isoforms (ACs 3, 7, and 8). The results, which document 21 exons in human and murine AC 6, human AC 3, 18 exons in AC 8, and 24 exons in AC 7, show substantial conservation of exon organization in the AC family and in particular regions of the AC protein. Application of such in silico methods should prove useful to characterize genes for other ACs and protein families and data provided here should facilitate studies of polymorphisms in AC genes.