Park D H, Stone D M, Baker H, Kim K S, Joh T H
Laboratory of Molecular Neurobiology, Cornell University Medical College, W.M. Burke Medical Research Institute, White Plains, NY 10605.
Brain Res Mol Brain Res. 1994 Mar;22(1-4):20-8. doi: 10.1016/0169-328x(94)90028-0.
Tryptophan hydroxylase (TPH) is the first and presumably rate-limiting enzyme in serotonin (5-HT) biosynthesis. End-product inhibition of rate-limiting enzymes is common and 5-HT is known to inhibit TPH activity in vivo. However, it is not known whether levels of 5-HT could also be involved in the regulation of the TPH gene. In order to determine whether TPH gene regulation is dependent on the 5-HT concentration, 5-HT levels were reduced by the administration of parachlorophenylalanine (PCPA). PCPA is a potent, specific and irreversible inhibitor of TPH activity which drastically reduces 5-HT concentration in the 5-HT neurons and terminals. When PCPA was administered, TPH activity in both cell bodies and nerve terminal areas, was reduced to 10% of control values and recovered to the control levels by day 7 in raphe nucleus, and within 14 days in the hypothalamus. In serotonergic terminal areas, 5-HT could not be detected immunohistochemically at day 1, but slowly recovered within 2 weeks. At all time points examined, aromatic L-amino acid decarboxylase (AADC) levels were not changed either in the cell body or terminal areas. The steady state levels of TPH mRNA estimated by in situ hybridization increased at day 1 and returned to control levels by day 4. AADC message levels were not altered throughout the periods. These data suggest that a decrease in 5-HT concentration may lead to an up-regulation of TPH gene transcription, by an, as yet, unknown mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
色氨酸羟化酶（TPH）是血清素（5-羟色胺，5-HT）生物合成过程中的首个且可能是限速酶。限速酶的终产物抑制作用很常见，而且已知5-HT在体内会抑制TPH活性。然而，尚不清楚5-HT水平是否也参与TPH基因的调控。为了确定TPH基因调控是否依赖于5-HT浓度，通过给予对氯苯丙氨酸（PCPA）来降低5-HT水平。PCPA是一种强效、特异性且不可逆的TPH活性抑制剂，它能大幅降低5-HT神经元和终末中的5-HT浓度。给予PCPA后，细胞体和神经终末区域的TPH活性均降至对照值的10%，在中缝核中到第7天恢复至对照水平，在下丘脑中则在14天内恢复。在5-羟色胺能终末区域，第1天时免疫组化检测不到5-HT，但在2周内缓慢恢复。在所有检测的时间点，细胞体或终末区域的芳香族L-氨基酸脱羧酶（AADC）水平均未改变。通过原位杂交估计的TPH mRNA稳态水平在第1天升高，并在第4天恢复至对照水平。整个期间AADC的信息水平均未改变。这些数据表明，5-HT浓度降低可能通过一种尚不清楚的机制导致TPH基因转录上调。（摘要截短至250字）
