Genetic Organization of the Serotonergic System

Abstract The serotonergic system consists of a number of genes and includes seven subfamilies of serotonin receptors (5-HT 1-7 ), with each subfamily revealing several subtypes. The system also includes tryptophan hydroxylase (TPH-1 and TPH-2) and monoamine oxidase (MAO) enzymes which are involved in synthesis and degradation of serotonin, respectively. Furthermore, serotonin transporter (SERT, 5-HTT) is an important protein in the scheme as it controls the amount of serotonin in the synapse. Brain-derived neurotrophic factor (BDNF) is included in this system, as it is known to modulate serotonin transporter function. Each of the genes and/or gene family is described in terms of their exon-intron organization, chromosomal localization, any alternative splice variants, and 5 '-flanking and promoter regions. Interestingly, most of these genes have been implicated in neuropsychiatric disorders; therefore, a discussion has been provided on significant functional polymorphisms that are associated with the phenotypes of interest. In general, all genes of the serotonergic system are organized into exons and introns except for the 5-HT 1 family of serotonin receptors, which are intronless and encoded by a single exon. Alternative splice forms have been identified in the 5-HT 2C , 5-HT 3A , 5-HT 4 , 5-HT 7 , TPH-1, 5-HTT and BDNF genes, whereas RNA editing isoforms are only observed with the 5-HT 2C receptor gene. The promoter and 5′-flanking regions have been characterized for the 5-HT 1A , 5-HT 2A , 5-HT 2C , 5-HT 3B , 5-HT 4 , 5-HT 7 , TPH-1, TPH-2, 5-HTT, MAOA and BDNF genes, with transcription factors (DNA binding proteins) identified in some of the genes to further elucidate transcription regulation. Evidently, the diverse and complex genetic structure/organization and regulation of the serotonin system is associated with the key actions as an important monoamine neurotransmitter in the central nervous system.