Compartmentalization of neuronal and peripheral serotonin synthesis in Drosophila melanogaster

Abstract

In Drosophila, one enzyme (Drosophila tryptophan-phenylalanine hydroxylase, DTPHu) hydroxylates both tryptophan to yield 5-hydroxytryptophan, the first step in serotonin synthesis, and phenylalanine, to generate tyrosine. Analysis of the sequenced Drosophila genome identified an additional enzyme with extensive homology to mammalian tryptophan hydroxylase (TPH), which we have termed DTRHn. We have shown that DTRHn can hydroxylate tryptophan in vitro but displays differential activity relative to DTPHu when using tryptophan as a substrate. Recent studies in mice identified the presence of two TPH genes, Tph1 and Tph2, from distinct genetic loci. Tph1 represents the non-neuronal TPH gene, and Tph2 is expressed exclusively in the brain. In this article, we show that DTRHn is neuronal in expression and function and thus represents the Drosophila homologue of Tph2. Using a DTRHn-null mutation, we show that diminished neuronal serotonin affects locomotor, olfactory and feeding behaviors, as well as heart rate. We also show that DTPHu functions in vivo as a phenylalanine hydroxylase in addition to its role as the peripheral TPH in Drosophila, and is critical for non-neuronal developmental events.

Role of the Phenylalanine-Hydroxylating System in Aromatic Substance Degradation and Lipid Metabolism in the Oleaginous Fungus Mortierella alpina

“…he phenylalanine-hydroxylating system catalyzes the irreversible hydroxylation of phenylalanine to tyrosine, which is the rate-limiting step in animal phenylalanine catabolism and protein and neurotransmitter biosynthesis and results in the formation of one molecule of fumarate and one of acetylcoenzyme A (CoA) from each molecule of phenylalanine (1,2). The animal phenylalanine-hydroxylating system consists of several essential components: phenylalanine hydroxylase (PAH) (EC 1.14.16.1), pterin-4␣-carbinolamine dehydratase (PCD) (EC 4.2.1.96), dihydropteridine reductase (DHPR) (EC 1.5.1.34), and the obligatory cofactors tetrahydrobiopterin (BH 4 ) and molecular oxygen (3,4) (Fig.…”

Serotonin and the search for the anatomical substrate of aggression

“…As in other species, serotonergic neurons in the fly nervous system display arbors of processes that ramify widely in multiple neuropil areas. Earlier studies from several laboratories, including ours, showed that manipulating total populations of 5HT neurons in Drosophila influence a wide variety of different behaviors [7][8][9][10][11][12] . How do serotonergic neurons function to exert such a wide spectrum of behavioral actions?…”

Big Lessons from Tiny Flies:<em> Drosophila Melanogaster </em>as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

“…Interestingly TPH is required for early development, implying that both serotonin and dopamine are required in non-neuronal cells during development itself [23,104,105]. TRH-null flies are viable and fertile with diminished locomotion and feeding behavior [105]. Overexpression of TRH in serotonergic neurons results in increased cytoplasmic serotonin levels, leading to spheroid formation, i.e.…”

“…anxiety-like behavior [109]. This may appear counterintuitive, because reduction in neuronal serotonin is associated with decreased locomotion [105], but it highlights the doubled-edged nature of transporter deficiency/inhibition: the plasmalemmal monoamine transporters are required for both, termination of synaptic signaling by removing the neurotransmitter and for replenishing the vesicular pool by operating in relay with VMAT. The symptoms of Parkinsonism, which are seen in the human dopamine transporter deficiency syndrome (see above), highlight the importance of the dopamine transporter in maintaining the vesicular dopamine pool.…”