Gene Structure and Processing of the 5HT2C PremRNA 2131 Gene Structure

The 5-HT2C receptor pre-mRNA is composed of at least seven exons (Fig. 21.1a). The entire human 5-HT2CR gene from exon I to exon VI spans around 326 kilobase (kb) of DNA. Current databases annotate six exons and five introns. Recently, a human 5-HT2C receptor mRNA was identified that contains a novel 91 nucleotide long alternatively spliced exon in the 5' untranslated region (UTR) between exon II and III (accession numbers M81778, DR003480). In addition, in mouse, a not previously annotated exon is located between Exon II and III of the mouse 5-HT2CR gene (mRNA accession number BC098327). This exon is unrelated to the human one. All introns of the serotonin receptor are larger than the mammalian average of 3365 nt (Thanaraj and Stamm 2003). The largest one is intron IV that spans about 117 kb. The 5' UTR of the gene comprises exons I and II and a part of exon III. The coding region of the 5-HT2CR cDNA spans from part of exon III to exon VI (Fig. 21.1b).

In contrast to many G-protein-coupled receptors that do not contain introns in their coding regions, the coding sequence of the human 5-HT2CR gene is interrupted by three introns. The long 3' UTR of the receptor is generated by exon VI. Key features of the gene structure, such as the positions of the intron-exon junctions as well as the promoter regions have been conserved between rodents and humans. This suggests that similar cis- and trans-acting elements regulate gene expression in both species. In its 5' UTR, the 5-HT2C receptor gene hosts at least one snoRNA (HBI-36) between exons II and III and two putative miRNAs hsa-mir-1264 and hsa-mir-1298. However, the function of these RNAs remains to be determined. Theoretically, the three alternative exons can be combined to generate nine mRNA isoforms. Combining these nine mRNA isoforms with 32 variants generated by pre-mRNA editing predicts that the 5-HT2CR gene can generate 288 mRNA isoforms. It is not clear whether all of these isoforms are actually generated. Detailed reverse transcription-polymerase chain reaction (RT-PCR) studies produced evidence for fragments of most of the isoforms a hsa-mir-1298

a hsa-mir-1298

Fig. 21.1 Gene structure of serotonin receptors. (a) Overview of pre-mRNAs generated from the serotonin receptor. Exons are indicated by boxes or a thick line and roman numerals. Introns are indicated as lines. Exons that contribute to the open reading frame are shaded. Splicing patterns are indicated by lines. Annotated and predicted RNA isoforms are indicated underneath the gene structure. Exon V undergoes alternative splicing. The splice sites I to III are indicated. The proximal, distal, and intronic splice sites I (P, D, and I) are indicated. (b) Protein isoforms and splicing events. The structure of the human 5-HT2CR receptor is indicated as in panel (a), and the intron and exon lengths are indicted. P and D indicate the location of proximal and distal splice sites, respectively. An arrow pointing towards AUG indicates the start codon of the longest open reading frame. UAA(P) and UAA(D) are the stop codons resulting from usage of the proximal and distal splice site. Exons are indicated as boxes with roman numerals. The mRNA isoforms and the resulting proteins are schematically shown. The shading reflects contribution of the different exons to the protein composition. Exon Vb encodes the second intracellular loop, and due to RNA editing, three amino acids, which are indicated as dots, are variable

Fig. 21.1 Gene structure of serotonin receptors. (a) Overview of pre-mRNAs generated from the serotonin receptor. Exons are indicated by boxes or a thick line and roman numerals. Introns are indicated as lines. Exons that contribute to the open reading frame are shaded. Splicing patterns are indicated by lines. Annotated and predicted RNA isoforms are indicated underneath the gene structure. Exon V undergoes alternative splicing. The splice sites I to III are indicated. The proximal, distal, and intronic splice sites I (P, D, and I) are indicated. (b) Protein isoforms and splicing events. The structure of the human 5-HT2CR receptor is indicated as in panel (a), and the intron and exon lengths are indicted. P and D indicate the location of proximal and distal splice sites, respectively. An arrow pointing towards AUG indicates the start codon of the longest open reading frame. UAA(P) and UAA(D) are the stop codons resulting from usage of the proximal and distal splice site. Exons are indicated as boxes with roman numerals. The mRNA isoforms and the resulting proteins are schematically shown. The shading reflects contribution of the different exons to the protein composition. Exon Vb encodes the second intracellular loop, and due to RNA editing, three amino acids, which are indicated as dots, are variable

(Burns et al. 1997; Niswender et al. 1999; Wang et al. 2000; Fitzgerald et al. 1999; Hackler et al. 2006). As the expression of these isoforms changes due to environmental stress and is altered in disease processes (Englander et al. 2005), their regulation has been studied in detail.

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Defeat Drugs and Live Free

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