O, and paresthesia. Positive results from two pivotal phase III trials of lasmitidan (Kuca et al., 2018; Loo et al., 2019) led to subsequent marketing and advertising approval in 2019. VII. 5-HT2A Receptors A. Introduction The 5-HT2A receptor (formerly 5-HT2) was first identified as a Carboxypeptidase A2 Proteins Recombinant Proteins binding web site in rat brain with high (nanomolar) affinity for [3H]spiperone and [3H]ketanserin and low (micromolar) affinity for 5-HT (Peroutka and Snyder,1979; Leysen et al., 1981). Soon soon after its discovery, the 5-HT2A receptor was located to mediate quite a few effects of 5-HT within the periphery, such as Ubiquitin Conjugating Enzyme E2 M Proteins custom synthesis platelet aggregation (De Clerck et al., 1982) and smooth muscle contraction (Cohen et al., 1981; Maayani et al., 1984; Engel et al., 1985). The peripheral 5-HT2A receptors had been originally classified as “D-type” 5-HT receptors depending on pharmacological evidence (Bradley et al., 1986). The 5-HT2A receptor was also the very first 5-HT receptor found to couple to stimulate phosphatidyl inositol hydrolysis (Conn and SandersBush, 1984). B. Cloning from the Gene The initial 5-HT2A receptor clone was isolated from rat brain cDNA libraries by homology screening determined by the sequence of structurally associated 5-HT2C receptor (Pritchett et al., 1988; Julius et al., 1990). Functional expression from the cloned receptor confirmed coupling to phosphoinositide hydrolysis and Ca21 mobilization. The human 5-HT2A receptor was subsequently cloned by Saltzman et al. (1991) and displayed 87 homology with the rat receptor. The receptor contains 471 amino acids, with five potential glycosylation web pages inside the N-terminal extracellular domain and 11 prospective phosphorylation internet sites in the C-terminal intracellular domain. The HTR2A gene encoding the human 5-HT2A receptor has been mapped to chromosome 13q14 21 (Sparkes et al., 1991). Evaluation of the genomic structure of the human 5-HT2A receptor revealed that it contains three exons separated by two introns, spanning far more than 20 kb (Chen et al., 1992; Stam et al., 1992). Other species from which the 5-HT2A receptor has been cloned include hamster (Van Obberghen-Schilling et al., 1991), mouse (Yang et al., 1992), and pig and rhesus monkey (Johnson et al., 1995) (Table 12). Sequence alignments for the 5-HT2A receptor from eight species are shown in Fig. eight. 1. Regulation of 5-HT2A Receptor Gene Expression. The structure in the 5-HT2A promoter region has been characterized in humans, rats, and mice; the promoters lack canonical TATA or CAAT boxes. Fragments of a 1.6-kb segment from the 59 flanking region from the human gene showed promoter activity when transfected into receptor-expressing human cell lines (Zhu et al., 1995). The human promoter sequence contains several transcription initiation internet sites, together with a number of binding web pages for transcription components, including simian virus 40 promoter element 1, polyomavirus enhancer activator three, cAMP response element, and E-box binding proteins. There was also evidence that the 59 flanking sequence includes an alternative promoter at the same time as a silencing element upstream in the translation commence codon. Falkenberg et al. (2011) subsequently demonstrated that the human promoter contains a glucocorticoid receptor (GR) binding website at position 21420. Furthermore, the A-allele in the 21438G/A (rs6311) polymorphism is believed to create a binding web-site for the5-HT Receptors TABLE 12 5-HT2A receptor genes, transcripts, and proteinsGene Organism Location Ensembl Gene ID mRNA Transcript NCBI RefSeq ID Base Pairs Receptor Protein NCBI Ref.