Interaction between Zinc, GPR39, BDNF and Neuropeptides in Depression

Abstract

As one of the most important elements in our body, zinc plays a part in both the pathophysiology of depression and the antidepressant response. Patients suffering from major depression show significantly reduced zinc levels, which are normalized following successful antidepressant treatment. Recent studies have shown the interaction between zinc, GPR39 and neuropeptides, including galanin and neuropeptide Y (NPY). The zinc-sensing receptor GPR39 forms heterotrimers with 5-HT_1A and the galanin receptor GalR₁ upon their co-expression in mammalian cells. The oligomerization of these heterotrimers is regulated by the zinc concentration, and this may have an influence on depressive-like behavior. The antidepressant-like effect of zinc is linked to elevated levels of brain-derived neurotrophic factor (BDNF) in brain structures associated with emotion, such as the hippocampus and the amygdala. BDNF regulates neuropeptides, including NPY, cholecystokinin (CCK), and substance P or galanin, which are also implicated in mood disorders. This review focuses for the first time on the interaction between zinc, the GPR39 zinc receptor, BDNF and selected neuropeptides in terms of depression in order to determine its possible role in the neuropharmacology of that illness.

Keywords: BDNF; GPR39; GPR39.; antidepressants; depression; neuropeptides; zinc.

Fig. (1)

The influence of zinc on CCK release via inhibition of NMDA receptor. Glutamate due to NMDA receptor can modulate the release of cholecystokinin (CCK). In the pathophysiology of depression, both the hihg CCK as well as high glutamate levels are observed (A). Zinc lowers glutamate levels by the inhibion of glutamatergic NMDA receptor and therefore may attenuate CCK realease (B). (A higher resolution/colour version of this figure is available in the electronic copy of the article).

Fig. (2)

A possible role of zinc in the oligomerization states among GPR39, GalR₁ and 5-HT_1A receptors. At high zinc concentrations 5-HT_1A-GPR39 heteromer exists as a dominant form. At low zinc concentration the expression of GPR39 decreases and 5-HT_1A-GPR39 heteromer is replaced by 5-HT_1A-GalR₁ heteromer. The oligomer 5-HT_1A-GPR39-GalR₁ seems to exsist as an intermediate form between 5-HT_1A-GPR39 and 5-HT_1A-GalR₁ heteromers at adequate zinc concentrations. (A higher resolution/colour version of this figure is available in the electronic copy of the article).