N-acetylserotonin activates TrkB receptor in a circadian rhythm.
Brain-derived neurotrophic factor (BDNF) is a cognate ligand for the TrkB receptor. BDNF and serotonin often function in a cooperative manner to regulate neuronal plasticity, neurogenesis, and neuronal survival. Here we show that NAS (N-acetylserotonin) swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. NAS, a precursor of melatonin, is acetylated from serotonin by AANAT (arylalkylamine N-acetyltransferase). NAS rapidly activates TrkB, but not TrkA or TrkC, in a neurotrophin- and MT3 receptor-independent manner. Administration of NAS activates TrkB in BDNF knockout mice. Furthermore, NAS, but not melatonin, displays a robust antidepressant-like behavioral effect in a TrkB-dependent way. Endogenous TrkB is activated in wild-type C3H/f(+/+) mice but not in AANAT-mutated C57BL/6J mice, in a circadian rhythm; TrkB activation is high at night in the dark and low during the day. Hence, our findings support that NAS is more than a melatonin precursor, and that it can potently activate TrkB receptor.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Sung-Wuk
SW
Jang
Xia
X
Liu
Sompol
S
Pradoldej
Gianluca
G
Tosini
Qiang
Q
Chang
P Michael
PM
Iuvone
Keqiang
K
Ye
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002460:Cell Line; D002940:Circadian Rhythm; D003863:Depression / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D020813:Receptor, trkB / Q000819:agonists* / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D012701:Serotonin; D020813:Receptor, trkB; D008550:Melatonin; C006389:N-acetylserotonin