PubMed · 4336931
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K Shima. 1971. [Glucagon].. https://pubmed.ncbi.nlm.nih.gov/4336931/
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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.
The circadian dynamics of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) were simulated in Paramecium multimicronucleatum. The mathematical functions determined closely mimic the Ca2+ dependence of adenylate cyclase (AC) and guanylate cyclase (GC) activities as documented in P. tetraurelia. Patterns of cAMP concentration ([cAMP]), cGMP concentration ([cGMP ]), and the ratio [cGMP]/[cAMP] were calculated with respect to Ca2+ concentrations ([Ca2+]) fluctuating sinusoidally with a period of 24 hours at three different levels: low, medium, and high. The functions displayed varying patterns of [cAMP] characteristic for [Ca2+] fluctuating at each level, while patterns of [cGMP] and [cGMP]/[cAMP] almost paralleled [Ca2+] fluctuations. Similar patterns were observed for actual [cAMP] and [cGMP] measured during the light/dark cycle in P. multimicronucleatum, grown in axenic media additionally containing [Ca2+] at 25 (low), 100 (medium), or 400 (high) microM, respectively. The coincidence between simulated and measured fluctuations of [cAMP] and [cGMP] suggests that the circadian fluctuations of intracellular [Ca2+] primarily stimulate activities of AC and GC via their different degrees of Ca2+ dependence, which are ultimately responsible for the circadian spatiotemporal organization of various physiological functions in Paramecium.
Previous results from this laboratory suggested that the same active conformation of the lutropin/choriogonadotropin receptor (LHR) is involved in the stimulation of G proteins and in triggering the internalization of the bound agonist. We have now analyzed two naturally occurring, constitutively active mutants of the human LHR. These mutations were introduced into the rat LHR (rLHR) and are designated L435R and D556Y. Cells expressing rLHR-D556Y bind human choriogonadotropin (hCG) with normal affinity, exhibit a 25-fold increase in basal cAMP and respond to hCG with a normal increase in cAMP accumulation. This mutation does not affect the internalization of the free receptor, but it enhances the internalization of the agonist-occupied receptors approximately 3-fold. Cells expressing rLHR-L435R also bind hCG with normal affinity, exhibit a 47-fold increase in basal cAMP, and do not respond to hCG with a further increase in cAMP accumulation. This mutation enhances the internalization of the free and agonist-occupied receptors approximately 2- and approximately 17-fold, respectively. We conclude that the state of activation of the rLHR can modulate its basal and/or agonist-stimulated internalization. Since the internalization of hCG is involved in the termination of hCG actions, we suggest that the lack of responsiveness detected in cells expressing rLHR-L435R is due to the fast rate of internalization of the bound hCG. The finding that membranes expressing rLHR-L435R (a system where internalization does not occur) respond to hCG with an increase in adenylyl cyclase activity supports this suggestion.