title: GPR39 Zn(2+)-sensing receptor: a new target in antidepressant development?
abstract: Zinc is a trace element released from glutamatergic terminals, and modulates the pre- and postsynaptic areas, giving a diverse biological response. Zinc is a natural ligand that inhibits the N-methyl-d-aspartate (NMDA) receptor and regulates the excessive release of glutamate. Moreover, zinc exhibits an antidepressant-like profile, as demonstrated in both preclinical and clinical studies. Recent reports indicate that the GPR39 Zn(2+)-sensing receptor is an important target for zinc "transmission" (its activation modulates/induces diverse biochemical pathways involved in neuroprotection). Preclinical studies provide evidence that zinc deficiency leads to depressive-like behavior related to down-regulation of the GPR39 Zn(2+)-sensing receptor. Zinc binds to the GPR39 and triggers signals, leading to CRE-dependent gene transcription, resulting in increases in proteins such as brain-derived neurotrophic factor (BDNF), that plays a pivotal role in antidepressant action. Chronic administration of many antidepressants induces GPR39 up-regulation, which suggests that the Zn(2+)-sensing receptor may be considered as a new target for drug development in the field of depression.
authors.affiliation: Department of Biochemical Toxicology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland. Electronic address: katarzyna.mlyniec@uj.edu.pl.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Młyniec
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82/III, A-6020 Innsbruck, Austria.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.affiliation: Department of Neuroscience and Pharmacology University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Kraków, Poland; Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007858:Learning; D008568:Memory; D058990:Molecular Targeted Therapy / Q000379:methods; D019964:Mood Disorders / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D015430:Weight Gain; D015431:Weight Loss; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; C495797:GPR39 protein, human; D018696:Neuroprotective Agents; D043562:Receptors, G-Protein-Coupled; D018698:Glutamic Acid; C579455:BDNF protein, human; D015032:Zinc
keywords: Antidepressants; BDNF; Depression; GPR39; NMDA; Zinc