Catecholamines and serotonin are differently regulated by tetrahydrobiopterin. A study from 6-pyruvoyltetrahydropterin synthase knockout mice.

Chiho Sumi-Ichinose,Hiroshi Ichinose,Masayo Kojima,Tamae Ohye,Toshiharu Nagatsu,Yasumichi Hagino,Fumi Urano,Risa Kuroda,Masahiro Tazawa,Hiroaki Shiraishi,Takahide Nomura

doi:10.1074/jbc.m102237200

Abstract

(6R)-L-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH), tryptophan hydroxylase, phenylalanine hydroxylase, and nitric-oxide synthase. These enzymes synthesize neurotransmitters, e.g. catecholamines, serotonin, and nitric oxide (NO). We established mice unable to synthesize BH4 by disruption of the 6-pyruvoyltetrahydropterin synthase gene, the encoded protein of which catalyzes the second step of BH4 biosynthesis. Homozygous mice were born at the almost expected Mendelian ratio, but died within 48 h after birth. In the brain of homozygous mutant neonates, levels of biopterin, catecholamines, and serotonin were extremely low. The number of TH molecules was highly dependent on the intracellular concentration of BH4 at nerve terminals. Alteration of the TH protein level by modulation of the BH4 content is a novel regulatory mechanism. Our data showing that catecholaminergic, serotonergic, and NO systems were differently affected by BH4 starvation suggest the possible involvement of BH4 synthesis in the etiology of monoamine-based neurological and neuropsychiatric disorders.

Highlights

(6R)-L-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH), tryptophan hydroxylase, phenylalanine hydroxylase, and nitric-oxide synthase
Ptps Knockout Mice Were Born but Died within 48 h of Birth—The Ptps gene was inactivated by homologous recombination in embryonic stem (ES) cells by use of a targeting vector, in which a 0.6-kb KpnI-BamHI Ptps genomic fragment containing exon 1 and a part of the 5Ј promoter region was replaced with the phosphoglycerate kinase (Pgk)-neomycin resistance gene (Fig. 1B)
There was no significant difference in TH staining on cell bodies, we found a striking difference in the terminal region

Summary

A STUDY FROM 6-PYRUVOYLTETRAHYDROPTERIN SYNTHASE KNOCKOUT MICE*

The DRD patients have both mutated and wild-type alleles of the GCH gene, and the resultant partial depletion of BH4 causes a shortage in DA in the nigrostriatal dopaminergic neurons in the brain of DRD patients [15] In these patients, there are no symptoms other than dystonia, and dysfunction of serotonergic neurons is not obvious, even though BH4 is a cofactor for both TH and TPH. There are no symptoms other than dystonia, and dysfunction of serotonergic neurons is not obvious, even though BH4 is a cofactor for both TH and TPH In this present study, for the first time, we established BH4deficient mice by disrupting the Ptps gene to investigate the effects of BH4 depletion on the animals and the involvement of BH4 in regulating neural systems. Our results indicated that BH4 distinctively regulates the synthesis of catecholamines altering the amount of TH protein and that of 5HT, and suggested that BH4 metabolism may be deeply involved in the pathophysiology of Parkinson’s disease, stress responses, and neuropsychiatric disorders

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION