Posttranslational regulation of TPH1 is responsible for the nightly surge of 5-HT output in the rat pineal gland.
Serotonin (5-hydroxytryptamine, 5-HT), a precursor for melatonin production, is produced abundantly in the pineal gland of all vertebrate animals. The synthesis of 5-HT in the pineal gland is rate limited by tryptophan hydroxylase 1 (TPH1) whose activity displays a twofold increase at night. Earlier studies from our laboratory demonstrate that pineal 5-HT secretion exhibits dynamic circadian rhythms with elevated levels during the early night, and that the increase is controlled by adrenergic signaling at night. In this study, we report that (a) 5-HT total output from the pineal gland and TPH1 protein levels both display diurnal rhythms with a twofold increase at night; (b) stimulation of cAMP signaling elevates 5-HT output in vivo; (c) 5-HT total output and TPH1 protein content in rat pineal gland are both acutely inhibited by light exposure at night. Consistent with these findings, molecular analysis of TPH1 protein revealed that (a) TPH1 is phosphorylated at the serine 58 in vitro and in the night pineal gland; and (b) phosphorylation of TPH1 at this residue is required for cAMP-enhanced TPH1 protein stability. These data support the model that increased nocturnal 5-HT synthesis in the pineal gland is mediated by the phosphorylation of TPH1 at the serine 58, which elevates the TPH1 protein content and activity at night.
Huang
Zheping
Z
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Liu
Tiecheng
T
Chattoraj
Asamanja
A
Ahmed
Samreen
S
Wang
Michael M
MM
Deng
Jie
J
Sun
Xing
X
Borjigin
Jimo
J
D000818:Animals; D047068:Arylalkylamine N-Acetyltransferase / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D002940:Circadian Rhythm; D000242:Cyclic AMP / Q000378:metabolism; D008027:Light; D008297:Male; D008550:Melatonin / Q000502:physiology; D017551:Microdialysis; D010766:Phosphorylation; D010870:Pineal Gland / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D012701:Serotonin; D000242:Cyclic AMP; D014365:Tryptophan Hydroxylase; C504570:tph1 protein, rat; C520223:Aanat protein, rat; D047068:Arylalkylamine N-Acetyltransferase; D008550:Melatonin