Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylat...

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Vydáno v:	Nature communications Ročník 10; číslo 1; s. 3924 - 14
Hlavní autoři:	Gorinski, Nataliya, Bijata, Monika, Prasad, Sonal, Wirth, Alexander, Abdel Galil, Dalia, Zeug, Andre, Bazovkina, Daria, Kondaurova, Elena, Kulikova, Elizabeth, Ilchibaeva, Tatiana, Zareba-Koziol, Monika, Papaleo, Francesco, Scheggia, Diego, Kochlamazashvili, Gaga, Dityatev, Alexander, Smyth, Ian, Krzystyniak, Adam, Wlodarczyk, Jakub, Richter, Diethelm W., Strekalova, Tatyana, Sigrist, Stephan, Bang, Claudia, Hobuß, Lisa, Fiedler, Jan, Thum, Thomas, Naumenko, Vladimir S., Pandey, Ghanshyam, Ponimaskin, Evgeni
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 02.09.2019 Nature Publishing Group Nature Portfolio
Témata:	14 14/19 38 38/89 631/378/1689/1414 631/45/612/194 64/60 82/29 82/58 9/10 9/74 Acyltransferase Acyltransferases - genetics Acyltransferases - metabolism Animal models Animals Brain Brain - metabolism Brain - physiopathology Cell Line, Tumor Depletion Depression - genetics Depression - metabolism Depression - physiopathology Depressive Disorder, Major - genetics Depressive Disorder, Major - physiopathology Forebrain Gene Expression Regulation Humanities and Social Sciences Humans Lipoylation Male Mental depression Mice, Inbred C57BL MicroRNAs - genetics miRNA multidisciplinary Palmitoylation Prefrontal cortex Rats, Wistar Receptor, Serotonin, 5-HT1A - genetics Receptor, Serotonin, 5-HT1A - metabolism Restoration Ribonucleic acid RNA Rodents Science Science (multidisciplinary) Serotonin Serotonin S1 receptors Suicide
ISSN:	2041-1723, 2041-1723
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Shrnutí:	The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD. Palmitoylation is a post translational modification that regulates GPCR activity. Here the authors show that palmitoylation of 5-HT1AR by the palmitoyltransferase enzyme ZDHHC21 contributes to depression-like behaviour in rodents and might be implicated in major depressive disorder.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-11876-5