PubMed · 45430
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P Greengard. Intracellular signals in the brain.. https://pubmed.ncbi.nlm.nih.gov/45430/
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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.
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The stimulation of adenylate cyclase by dopamine and various beta-adrenergic agonists has been investigated in homogenates from 3 areas of cat brain: the cerebral cortex, cerebellum and hippocampus. The purpose of the study was to determine whether the beta-arenergic receptors coupled to adenylate cyclase could be classified as either beta 1 and beta 2 subtypes in the different regions studied. The stimulation of adenylate cyclase by the beta-adrenergic agonist, (-)isoproterenol (5 X 10(-6) M), was completely blocked by the specific beta-adrenergic antagonist, (p)alprenolol (1-(-5) M), but not by the dopaminergic antagonist, fluphenazine (10(-5) M), whereas the stimulation of adenylate cyclase by (-)epinephrine (10(-4) M) was blocked to varying extents by these two drugs in each of the 3 regions studied. The (-)epinephrine effect was always blocked in the combined presence of (p)alprenolol and fluphenazine. The adenylate cyclase stimulation by (p)epinephrine which is not blocked by (p)alprenolol was due to interaction of (p)epinephrine with a dopaminergic-sensitive adenylate cyclase which has been characterized in cerebral cortex, hippocampus and cerebellum. Regional differences in the affinity of beta-adrenergic-sensitive adenylate cyclase for various agonists were investigated in the presence of fluphenazine (10(-5) M). In the cerebellum the potency order was (+/-)protokylol greater than (+/-)hydroxybenzylisoproterenol greater than (+/-)isoproterenol greater than (-)epinephrine greater than (+/-)salbutamol greater than (-)norepinephrine, indicating the presence of a beta 2-adrenergic receptor. In the cerebral cortex the potency order was (-)isoproterenol greater than +/-)protokylol greater than (+/-)hydroxybenzylisoproterenol greater than (-)epinephrine = (-)norepinephrine ((+/-)salbutamol being inactive). A similar pattern was found in the hippocampus indicating the presence of a beta 1-adrenergic receptor in these two regions. (+/-)Salbutamol was a partial agonist in the cerebellum and a competitive antagonist in the cerebral cortex. The ratio of the antagonist potencies of (+/-)practolol and (+/-)butoxamine preferential beta 1- and beta 2-adrenergic antagonists respectively, to block the stimulation of adenylate cyclase was 25 in the cerebellum, compared to 0.5 in the cerebral cortex and 1.6 in the hippocampus. These results confirm the presence of a beta 2 subtype of receptor coupled to adenylate cyclase in the former and beta 1 subtypes in the latter two regions. The comparison between the affinities of a series of beta-adrenergic agonists and antagonists for the beta-adrenergic receptors coupled with an adenylate cyclase in cerebral cortex and cerebellum with their affinities for well characterized beta 2-adrenergic receptors in lung and beta 1-adrenergic receptor in heart substantiated this conclusion.