title: The involvement of the GPR39-Zn(2+)-sensing receptor in the pathophysiology of depression. Studies in rodent models and suicide victims.
abstract: Zinc is one of the most important trace elements in our body. Patients suffering from depression show lower serum zinc levels compared to healthy controls. Zincs antagonism to the glutamatergic system seems to be responsible for mood recovery. Recent years have shown that zinc may regulate neurotransmission via the metabotropic GPR39 receptor. Activation of the GPR39-Zn(2+)-sensing receptor (GPR39) triggers diverse neuronal pathways leading to a cAMP-responsive element binding the protein (CREB) expression, which then induces synthesis of the brain-derived neurotrophic factor and, in turn, activation of the Tropomyosin receptor kinase B (TrkB) receptor. In the present study, we investigated the alteration of the GPR39 in different models of depression, such as zinc deficiency and olfactory bulbectomy and in suicide victims. Additionaly, we focused on CREB-BDNF/TrkB under zinc deficient conditions in mice. To demonstrate depressive-like behaviour, a standard and modified forced swim test (FST) was performed. To evaluate expression of GPR39, CREB, BDNF and TrkB, Western Blot analysis was used. Zinc deficient mice and rats showed decreased GPR39 expression in the hippocampus and frontal cortex. A decreased level of hippocampal and cortical GPR39 was also observed in suicide victims. In contrast, increased GPR39 in the hippocampus of olfactory bulbectomized rats was observed. Additionally, we found a decreased expression of CREB, BDNF and TrkB only in the hippocampus of zinc-deficient mice. Our present study demonstrates the associacion of the GPR39 Zn(2+)-sensing receptor in the pathomechanism of depression. Down-regulation of CREB, BDNF, TrkB and GPR39 receptor found under zinc-deficient conditions in the hippocampus, may play an important role in the pathophysiology of mood disorders, since most of patients suffering from depression show lower serum zinc.
authors: Department of Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, PL 31-343 Kraków, Poland. Electronic address: katarzyna.mlyniec@uj.edu.pl.
authors: Katarzyna
authors: K
authors: Młyniec
authors: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, PL 31-343 Kraków, Poland.
authors: Urszula
authors: U
authors: Doboszewska
authors: Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, PL 31-343 Kraków, Poland.
authors: Bernadeta
authors: B
authors: Szewczyk
authors: Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, PL 31-343 Kraków, Poland; Centre of Applied Biotechnology and Basic Sciences, University of Rzeszów, Kolbuszowa, Poland.
authors: Magdalena
authors: M
authors: Sowa-Kućma
authors: Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, PL 31-343 Kraków, Poland.
authors: Paulina
authors: P
authors: Misztak
authors: Department of Analytical Chemistry Faculty of Chemistry, Jagiellonian University, Krakow, Poland; Laboratory of High Resolution Mass Spectrometry, Regional Laboratory of Physicochemical Analysis and Structural Research, Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
authors: Wojciech
authors: W
authors: Piekoszewski
authors: Department of Forensic Medicine, Jagiellonian University Medical College, Kraków, Poland.
authors: Franciszek
authors: F
authors: Trela
authors: Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Kraków, Poland.
authors: Beata
authors: B
authors: Ostachowicz
authors: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Institute of Pharmacology, Polish Academy of Sciences and Center of Excellence in Neuropsychopharmacology, Smętna 12, PL 31-343 Kraków, Poland.
authors: Gabriel
authors: G
authors: Nowak
mesh_terms: D000328:Adult; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003866:Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009830:Olfactory Bulb / Q000503:physiopathology / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013405:Suicide; D015032:Zinc / Q000172:deficiency
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C495797:GPR39 protein, human; C512928:GPR39 protein, mouse; C535178:GPR39 protein, rat; D043562:Receptors, G-Protein-Coupled; D020813:Receptor, trkB; D015032:Zinc
keywords: BDNF; CREB; Depression; GPR39; TrkB; Zn(2+)-sensing receptor