PubMed · 2879051
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Y Nakase. 1986. [Pertussis].. https://pubmed.ncbi.nlm.nih.gov/2879051/
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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.
We developed previously VPAC(1) [vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptor]>VPAC(2) receptor selective ligands. Replacement of the VIP-Thr(11) by an Arg(11) in these ligands contributed to their selectivity: Arg(11)-VIP had a 200-fold lower affinity when compared with VIP at VPAC(2) receptors as opposed to 3- to 5-fold higher affinity at VPAC(1) receptors. Comparison of the binding and functional properties of related VIP analogues suggested that the VPAC(1) selectivity of Arg(11)-VIP was due to the loss of a hydrogen bond between the hydroxy group of Thr residue and the VPAC(2) receptor, steric hindrance between the Arg side chain and the VPAC(2) receptor and charge attraction by the VPAC(1) receptor. Comparison of the ability of VIP analogues to activate adenylate cyclase through chimaeric VPAC(1)/VPAC(2) and VPAC(2)/VPAC(1) receptors indicated that the first extracellular receptor loop carried most of the VPAC(2) receptors' ability to discriminate VIP from Arg(11)-VIP. Based on results obtained for a truncated VPAC(2) receptor and the closely related PACAP-preferring receptor (PAC(1)) and secretin receptors, we hypothesized that Thr(11) interacted with the VPAC(2) receptor Tyr(184) (similar to the VPAC(1) receptor Phe(200) residue). The Y184F (Tyr(184)-->Phe) VPAC(2) mutant lost the ability to discriminate VIP from Val(11)-VIP, and the F200Y VPAC(1) mutant acquired the ability to discriminate the natural peptide from Val(11)-VIP. These results support the hypothesis that the hydroxy group of the native VIP-Thr(11) side chain can indeed form a hydrogen bond with the Tyr side chain in the VPAC(2) receptor.
BACKGROUND: Cannabinoids exert a wide spectrum of effects in men including alterations in the reproductive system. To date, two types of cannabinoid receptors have been cloned in humans, namely CB(1) and CB(2) belonging to the G protein-coupled receptor superfamily. Although cannabinoids have functional and morphologic effects in the prostate gland, the expression of cannabinoid receptors in this tissue has never been investigated. The aim of this study was to analyze the expression of cannabinoid receptors in the human prostate gland and their regulatory effects on adenylyl cyclase activity. METHODS: To investigate the existence of cannabinoid receptors in prostate, we used various methods, including reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. Adenylyl cyclase activity was analyzed by measuring the cAMP produced by means of a competitive assay by using PKA. RESULTS: Both mRNA for CB(1) and the corresponding protein are expressed in the human prostate gland at a level comparable with the receptor expressed in cerebellum. The molecular mass of the protein estimated from Western blot analysis was 58 kDa, which is in concordance with previous data for CB(1) in other tissues. Immunohistochemical studies show that CB(1) is preferentially expressed in the epithelia of the prostate. The cannabinoid receptor expressed in the prostate negatively regulates adenylyl cyclase activity through a pertussis toxin-sensitive protein.