Functional polymorphisms of the brain serotonin synthesizing enzyme tryptophan hydroxylase-2

The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in various physiological functions in both peripheral and central nervous systems (CNS). Many neuropsychiatric disorders, including depression [ 1 – 4 ], schizophrenia [ 4 – 6 ], aggression and suicidal behavior [ 1 , 6 ], attention-deficit/hyperactivity disorder (ADHD) [ 7 – 9 ], obsessive-compulsive disorder [ 10 ] and autism [ 11 ] have been suggested to be related to the dysregulation of brain serotonergic neurotransmission. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in 5-HT synthesis and belongs to the superfamily of aromatic amino acid hydroxylase, which also includes tyrosine hydroxylase (TH) and phenylalanine hydroxylase (PAH). TPH, TH and PAH share considerable structural similarity and require the same co-factor (Fe 2+ ) and cosubstrate (tetrahydrobiopterin, BH4) for function [ 12 ]. While TH and PAH are each encoded by a single gene, there has been evidence suggesting that two genes may encode TPH [ 13 , 14 ]. The recent identification of a TPH2 gene [ 15 ] has demonstrated that this is indeed the case. The well-characterized TPH1 was identified 4 decades ago [ 16 ] and has recently been shown to be essentially peripheral, being expressed predominantly in the pineal gland and enterochromaffin cells of the gut [ 15 , 17 – 19 ]. In contrast to the results of RNase protection assay [ 15 ] and in situ hybridization study [ 19 ], Zill et al. [ 20 ] recently reported the expression of TPH1 messenger RNA (mRNA) in several brain regions in post-mortem human brains. However, further studies may be needed to examine whether such TPH1 expression represents the pineal projections in these brain regions [ 21 ], as serotonin Nacetyltransferase (AANAT), the rate-limiting enzyme in melatonin synthesis, has been shown to be expressed also in certain brain regions [ 21 ]. TPH2 , however, is expressed predominantly in serotonergic neurons of the raphe nuclei [ 15 , 19 ] and in the peripheral myenteric neurons in the gut [ 18 ]. To date, TPH2 has been identified and cloned in human, mice, rat, chicken, zebrafish, torafugu and fruit fly (gene accession numbers: NM_173353 [human], NM_173391 [mouse], NM_173839 [rat], NM_001001301 [chicken], NM_214795 [zebrafish], AY616189 [torafugu]) [ 15 , 22 , 23 ]. This paper will summarize some recent findings about TPH2 , and focus on the functional analysis of TPH2 and its potential contribution to the dysregulation of brain serotonin homeostasis associated with the pathophysiology of neuropsychiatric disorders.