Fig. 2.

Conservation of serotonin pathway machinery. a Mammalian serotonin pathway. TPH Tryptophan hydroxylase synthesizes Serotonin (5-HT) from tryptophan. There are 2 mammalian TPH isoforms: TPH-1 and TPH-2 (Walther al. 2003). The VMAT vesicular monoamine transporter pumps 5-HT from the cytoplasm into either small synaptic vesicles or dense core vesicles (Liu and Edwards 1997). There are 2 mammalian VMAT proteins: VMAT1, found in neuroendocrine cells, and VMAT2, expressed in all CNS serotonergic neurons (Erickson et al. 1992; Weihe et al. 1994). Post-synaptic neurons express 7 classes of serotonin receptors. 5-HT₁, 5-HT₂, 5-HT₄, 5-HT₅, 5-HT₆, 5-HT₇ are GPCR G-protein-couple receptors (Hartig 1997). 5-HT₃ is a ligand-gated sodium channel with no orthologue in the invertebrates (Hanna et al. 2000). SERT Serotonin transporter protein removes 5-HT from the synaptic cleft (Chang et al. 1996). 5-HT is degraded by MAO monoamine oxidase, which catalyzes oxidative deamination of 5-HT. There are 2 forms: MAO A and MAO B (Bach et al. 1988). b D. melanogaster serotonin pathway. Serotonin (5-HT) is synthesized by 2 tryptophan hydroxylase homologues: DTRHn (hydroxylates tyryptophan) and DTPHu (hydroxylates both tryptophan and phenylalanine) (Neckameyer and White 1992; Neckameyer et al. 2007). 5-HT is packaged into vesicles with DVMAT, homologous to mammalian VMAT1 and VMAT2 (Greer et al. 2005). 4 classes of serotonin receptors have been identified: 5-HT₇Dro is functionally similar to 5HT₇ (Becnel et al. 2011). 5-HT_1ADro and 5-HT_1BDro are most functionally similar to 5HT₁ (Gerhardt et al. 1996). 5-HT₂Dro is related in structure and pharmacology to 5-HT₂ (Colas et al. 1995). 5-HT is removed from the synaptic cleft by DSERT, homologous to mammalian SERT (Demchyshyn et al. 1994). c C. elegans serotonin pathway. Serotonin (5-HT) is synthesized by TPH-1 (Sze et al. 2000). 5-HT is packaged with VMAT, homologous to mammalian VMAT1 and VMAT2 (Duerr et al. 1999). Five serotonin receptors have been identified in C. elegans. Four are G-protein coupled receptors (GPCR): SER-4 resembles 5HT₁ (Olde and McCombie 1997), SER-5 has only sequence similarity to 5-HT₆ (Hapiak et al. 2009), SER-1, a 5HT₂-like receptor (Hamdan et al. 1999) and SER-7, homologous to 5-HT₇ mammalian receptor (Hobson et al. 2003). MOD-1 is a 5-HT gated chloride channel not found in mammals (Ranganathan et al. 2000). 5-HT is removed from the synaptic cleft by MOD-5, a serotonin reuptake transporter (Cooper et al. 1996). MOD-5 is homologous to mammalian SERT (Ranganathan et al. 2001). Once removed from the cleft, 5HT is degraded by an enzyme homologous to monoamine oxidase (Weyler 1992)