Odor discrimination by G protein-coupled olfactory receptors

The vertebrate olfactory system possesses a remarkable capacity to recognize and discriminate a variety of odorants by sending the coding information from peripheral olfactory sensory neurons in the olfactory epithelium to the olfactory bulb of the brain. The recognition of odorants appear to be mediated by a G protein-coupled receptor superfamily that consists of approximately 1% of total genes in vertebrates. Since the first discovery of the olfactory receptor gene superfamily in the rat, similar chemosensory receptors have been found in various species across different phyla. The functions of these receptors, however, had been uncharacterized until the recently successful functional expression and ligand screening of some olfactory receptors in various cell expression systems. The functional cloning of odorant receptors from single olfactory neurons allowed for the identification of multiple receptors that recognized a particular odorant of interest. Reconstitution of the odorant responses demonstrated that odorant receptors recognized various structurally-related odorant molecules with a specific molecular receptive range, and that odor discrimination is established based on a combinatorial receptor code model in which the identities of different odorants are encoded by a combination of odorant receptors. The receptor code for an odorant changes at different odorant concentrations, consistent with our experience that perceived quality of an odorant changes at different concentrations. The molecular bases of odor discrimination at the level of olfactory receptors appear to correlate well with the receptive field in the olfactory bulb where the input signal is further processed to create the specific odor maps.     

低剂量辐射对小鼠松果腺cAMP水平的影响

采用昆明系小鼠,全身照射低剂量Ｘ射线,剂量为５０￣５００ｍＧｙ,剂量率为１２．５ｍＧｙ／ｍｉｎ,照射后２４ｈ,检测松果腺ｃＡＭＰ含量变化,结果表明５０￣１００ｍＧｙＸ射线全身照射可使松果腺ｃＡＭＰ含量明显升高,其中７５ｍＧｙ组ｃＡＭＰ水平为最高（为假照射组的３．７倍ｐ〈０．００１）。而高剂量的对比观察１￣４Ｇｙ照射,松果腺ｃＡＭＰ水平呈降低趋势,其中２、４Ｇｙ照射组较假照射组明显减少（ｐ〈０．０５     

Hippocampal–prefrontocortical circuits: PKA inhibition in the prefrontal cortex impairs delayed nonmatching in the radial maze in rats.

Recent findings implicate the prefrontal cortex (PFC) and, in particular, frontocortical dopamine acting at D1-like receptors, in working memory. However, the mechanisms underlying this function of dopamine remain unknown. The present studies evaluated the hypothesis that dopamine contributes to working memory through its action on the 2nd messenger cyclic 3',5'-adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA). Thus, rats were trained to perform random foraging or delayed (30 min) nonmatching-to-position (delayed win-shift) tasks on the radial maze. With hippocampal output to the frontal cortex disconnected by injecting lidocaine (20 μg/0.5 μl) unilaterally into the ventral subiculum, contralateral frontocortical injections of lidocaine (20 μg/0.5 μl) or the D1-like dopamine receptor antagonist SCH 23390 (0.5 μg/0.5 μl) impaired delayed win-shift but not random foraging, replicating previous findings. In similarly disconnected rats, frontocortical injections of the PKA inhibitor Rp-cAMPS (5.0 and 10.0, but not 1.0, μg/0.5 μl) selectively impaired delayed nonmatching-to-position. Results suggest that activation of the cAMP-PKA pathway by dopamine acting at D1-like receptors in the frontal cortex is necessary for working memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cyclic Adenosine Monophosphate Eliminates Sex Differences in Estradiol-Induced Elastin Production from Engineered Dermal Substitutes

Lack of adult cells’ ability to produce sufficient amounts of elastin and assemble functional elastic fibers is an issue for creating skin substitutes that closely match native skin properties. The effects of female sex hormones, primarily estrogen, have been studied due to the known effects on elastin post-menopause, thus have primarily included older mostly female populations. In this study, we examined the effects of female sex hormones on the synthesis of elastin by female and male human dermal fibroblasts in engineered dermal substitutes. Differences between the sexes were observed with 17β-estradiol treatment alone stimulating elastin synthesis in female substitutes but not male. TGF-β levels were significantly higher in male dermal substitutes than female dermal substitutes and the levels did not change with 17β-estradiol treatment. The male dermal substitutes had a 1.5-fold increase in cAMP concentration in the presence of 17β-estradiol compared to no hormone controls, while cAMP concentrations remained constant in the female substitutes. When cAMP was added in addition to 17β-estradiol and progesterone in the culture medium, the sex differences were eliminated, and elastin synthesis was upregulated by 2-fold in both male and female dermal substitutes. These conditions alone did not result in functionally significant amounts of elastin or complete elastic fibers. The findings presented provide insights into differences between male and female cells in response to female sex steroid hormones and the involvement of the cAMP pathway in elastin synthesis. Further explorations into the signaling pathways may identify better targets to promote elastic fiber synthesis in skin substitutes.     

Whole Exome Sequencing for a Patient with Rubinstein-Taybi Syndrome Reveals de Novo Variants besides an Overt CREBBP Mutation

Rubinstein-Taybi syndrome (RSTS) is a rare condition with a prevalence of 1 in 125,000–720,000 births and characterized by clinical features that include facial, dental, and limb dysmorphology and growth retardation. Most cases of RSTS occur sporadically and are caused by de novo mutations. Cytogenetic or molecular abnormalities are detected in only 55% of RSTS cases. Previous genetic studies have yielded inconsistent results due to the variety of methods used for genetic analysis. The purpose of this study was to use whole exome sequencing (WES) to evaluate the genetic causes of RSTS in a young girl presenting with an Autism phenotype. We used the Autism diagnostic observation schedule (ADOS) and Autism diagnostic interview revised (ADI-R) to confirm her diagnosis of Autism. In addition, various questionnaires were used to evaluate other psychiatric features. We used WES to analyze the DNA sequences of the patient and her parents and to search for de novo variants. The patient showed all the typical features of Autism, WES revealed a de novo frameshift mutation in CREBBP and de novo sequence variants in TNC and IGFALS genes. Mutations in the CREBBP gene have been extensively reported in RSTS patients, while potential missense mutations in TNC and IGFALS genes have not previously been associated with RSTS. The TNC and IGFALS genes are involved in central nervous system development and growth. It is possible for patients with RSTS to have additional de novo variants that could account for previously unexplained phenotypes.     

The effect of adrenergic receptor—adenyl cyclase system on myocardial ischemic preconditioning in rats

In order to study the effects of every part of adrenergic reccptor-adenyl cyclase system on ischemic preconditioning of myocardium in rats in vivo, SD rats were divided into three groups: IP group, I/R group and CON group. Rats were received surgical procedure and undergone left coronary artery occlusion and reperfu-sion. Hearts were extracted to analyze the infarct size by TTC staining, to measure serum myocardial enzymes, to study β-AR Bmax and Kd by radioligand binding assay of receptors (RAB), and to check the activity of AC and the content of cAMP by ra-dioimmunoassay (RIA). The infarct area was found much smaller in IP group than I/R group (p <0.001); CK,CK-MB and LDH were found significantly higher in I/R group (p <0.001). The Bmax of β-AR in IP group were higher than in I/R group (p <0.001). No difference of Kd could be seen between IP and I/R group. In IP group, the activity of AC and the content of cAMP were higher than I/R group (p <0.05 and 0.001, respectively). It is concluded that ischemi     

Activation of trehalase during growth induction by nitrogen sources in the yeast Saccharomyces cerevisiae depends on the free catalytic subunits of camp-dependent protein kinase,but not on functional ras proteins

Addition of a nitrogen-source to glucose-repressed, nitrogen-starved G0 cells of the yeast Saccharomyces cerevisiae in the presence of a fermentable carbon source induces growth and causes within a few minutes a five-fold, protein-synthesis-independent increase in the activity of trehalase. Nitrogen-activated trehalase could be deactivated in vitro by alkaline phosphatase treatment, supporting the idea that the activation is triggered by phosphorylation. Yeast strains containing only one of the three TPK genes (which encode the catalytic subunit of cAMP-dependent protein kinase) showed different degrees of nitrogen-induced trehalase activation. The order of effectiveness was different from that previously reported for glucose-induced activation of trehalase in glucose-derepressed yeast cells. Further reduction of TPK-encoded catalytic subunit activity by partially inactivating point mutations in the remaining TPK gene further diminished nitrogen-induced trehalase activation, while deletion of the BCY1 gene (which encodes the regulatory subunit) in the same strains resulted in an increase in the extent of activation. Deletion of the RAS genes in such a tpk^w1 bcy1 strain had no effect. These results are consistent with mediation of nitrogen-induced trehalase activation by the free catalytic subunits alone. They support our previous conclusion that cAMP does not act as second messenger in this nitrogen-induced activation process and our suggestion that a novel nitrogen-induced signaling pathway integrates with the cAMP pathway at the level of the free catalytic subunits of protein kinase A. Western blot experiments showed that the differences in the extent of trehalase activation were not due to differences in trehalase expression. On the other hand, we cannot completely exclude that protein kinase A influences the nitrogen-induced activation mechanism itself rather than acting directly on trehalase. However, any such alternative explanation requires the existence of an additional, yet unknown, mechanism for activation of trehalase besides the well-established regulation by protein kinase A.