Five adenosines within the coding sequence of the serotonin 2C receptor (5-HT2C) pre-mRNA are converted to inosines by RNA editing (named A, B, C' (E), C, and D sites). In human prefrontal cortex (PFC), the most abundant 5-HT2C mRNA sequences result from editing at the A site, or from the editing combinations AC'C, ABCD, and ABD. In suicide victims with a history of major depression, C' site editing is significantly increased, D site editing is significantly decreased, and the C site shows a trend toward increased editing. Treatment of mice with the antidepressant drug fluoxetine (Prozac) causes changes in C', C, and D site editing that are exactly opposite to those seen in suicide victims. Thus, one outcome of fluoxetine treatment may be to reverse the abnormalities in 5-HT2C pre-mRNA editing seen in depressed suicide victims.
Serotonin 2C (5-HT 2C ) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, CЈ, C, and D editing sites) to inosines. Editing of two of these sites (CЈ and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT 2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonindependent manner. In serotonin-depleted mice, CЈ-and C-site editing is significantly decreased. This results in an increased expression of 5-HT 2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT 2A/2C agonist (Ϯ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the CЈ site and leads to increased expression of 5-HT 2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT 2C mRNA levels. These data indicate that editing of 5-HT 2C pre-mRNA is a mechanism that retains basic response properties of 5-HT 2C receptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing. Key words: serotonin; 5-HT 2C receptor; RNA editing; forebrain neocortex; 5-HT depletion; 5-HT 2A/2C agonistThe conversion of adenosine (A) to inosine (I) by ADARs (adenosine deaminases that act on RNA) is the most widespread editing in higher eukaryotes (Bass, 2002). Although the total inosine content of rat brain poly(A ϩ ) RNA predicts that one inosine occurs approximately once every 17,000 nucleotides (Paul and Bass, 1998), only a few neuronal substrates for A to I editing have been identified. They include the serotonin 2C (5-HT 2C ) receptor, the first G-protein-coupled receptor known to be edited. In 5-HT 2C pre-mRNA, a total of five closely spaced adenosines (named A, B, CЈ, C, and D editing sites) located within a sequence that encodes the second intracellular loop of the receptors protein can be converted to inosines (Burns et al., 1997;Niswender et al., 1999). This editing can change up to three triplet codons and has the potential to generate 24 different protein isoforms. Compared with nonedited 5-HT 2C receptors, the receptor isoform that results from editing at the ABCD sites and other partially edited isoforms that are edited at the CЈsite but not the C site exhibit a fourfold reduction in the efficiency to activate G-protein in response to agonist stimulation. This reduction is even higher (15-to 25-fold) for completely edited isoforms and other partially edited isoforms that are edited at both CЈ and C sites. Other partially edited isoforms that are not edited at the CЈ and/or C site appear to be fully functional (Niswender et al., 1999;Wang et al., 2000).At present, the significance of 5-HT 2C pre-mRNA editing in vivo is still unknown. However, a recent study indicates that this editing is regulated and suggests that this regulation is sensitive ...
When small amounts of a good hydrogen-bond acceptor such as pyridine or THF are added to a nonpolar swelling solvent such as chlorobenzene or toluene, there is a very rapid increase in coal swelling with increasing acceptor concentration which presently almost levels off. When swelling is plotted against pyridine concentration, the result is what appears to be a titration curve. This curve permits an estimation of the number of hydrogen-bond cross-links in the coal. We believe that this behavior is due to the selective association between the hydrogen-bond acceptor (e.g., pyridine) and hydroxyl groups which are cross-links between macromolecular chains in the coal. The selectivity of the acceptor for cross-linking hydroxyls over other hydroxyls (more favorable free energy for association of pyridine with the cross-linking hydroxyl) is due to the much more favorable entropy change which occurs when one of these cross-links is disrupted by formation of a new hydrogen bond to pyridine. This disruption frees a portion of the coal to adopt many more possible conformations lending to the favorable entropy change. This model leads directly to the prediction that this titration curve will be independent of the hydrogen-bond acceptor, a prediction which is verified by the identical curves observed using pyridine or THF in chlorobenzene with Illinois No. 6 coal. Changing the nonpolar solvent does not result in a change in the number of hydrogen bonds in agreement with this model. About 1/3 of the hydroxyl groups in Illinois No. 6 coal form network-active hydrogen bonds (cross-links) and there are about 1.7 hydrogen bonds per 100 carbon atoms. In the higher rank Pittsburth No. 8 coal there are approximately 0.3 cross-linking hydrogen bonds per 100 carbon atoms.
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