Article Figures & Data
Figures
- Fig. 1.
The role of Ca2+ signaling in depression. Increased glutamate that occurs during depression enhances Ca2+ through the activation of NMDAR Ca2+ channels and by activation of the metabotropic glutamatergic receptor 5 (mGluR5) that is coupled to phospholipase C (PLC) to hydrolyze phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P2) to form inositol 1,4,5-trisphosphate (InsP3) that releases Ca2+ from the endoplasmic reticulum (ER). Acetylcholine acting through the muscarinic 1 (M1) receptor also stimulates the formation of InsP3. The hydrolysis of PIP2, which normally acts to open the Kv7 2/3 channels that hyperpolarizes the neuronal membrane, acts to close these K+ channels and the membrane depolarizes, resulting in enhanced neuronal excitability. Vitamin D acts to reduce Ca2+ signaling by acting through the vitamin D receptor (VDR) to increase the expression of the Ca2+ buffer calbindin and it increases expression of the plasma membrane Ca2+ pump (PMCA) and the sodium/Ca2+ exchanger 1 (NCX1). Vitamin D also reduces the level of Ca2+ by reducing the expression of the L-type CaV1.2 channel.
- Fig. 2.
Vitamin D prevents the onset of depression by activating a number of processes that are critical to maintain normal healthy neurons. Vitamin D enters the nucleus where it associates with the retinoid X receptor (RXR) and then binds to the vitamin D response element (VDRE), which is located on a large number of genes. It maintains Ca2+ homeostasis by inducing the expression of calbindin, parvalbumin, Na+/Ca2+ exchanger 1 (NCX1), and the plasma membrane Ca2+-ATPase (PMCA) pump. It also regulates Ca2+ by reducing the expression of the CaV1.2 calcium channel. It activates expression of many antioxidant genes such as the nuclear factor-erythroid-2-related factor 2 (NRF2), γ-glutamyl transpeptidase (γ-GT), glutamate cysteine ligase (GCLC), glutathione reductase (GR), glutathione peroxidase (Gpx). It controls the formation of serotonin by increasing the level of tryptophan hydroxylase 2 (TPH2) while repressing tryptophan hydroxylase1 (TPH1). It reduces inflammation by reducing the expression of inflammatory cytokines. It regulates the expression of many mitochondrial proteins that maintain normal mitochondrial respiration. Finally, it regulates the epigenetic landscape by promoting the expression of DNA demethylases such as Jumonji domain-containing protein 1A and 3 (JMJD1A, JMJD3) and lysine-specific demethylase 1 and 2 (LSD1, LSD2).
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- Article
- Abstract
- I. Introduction
- II. Dysfunctional Neural Circuits in Depression
- III. Tonic Excitatory Drive and Depression
- IV. Enhanced Neuronal Ca2+ Signaling in Depression
- V. Inflammation and Depression
- VI. Vitamin D and Depression
- VII. Depression and Alzheimer’s Disease
- VIII. Conclusion
- Authorship Contributions
- Footnotes
- Abbreviations
- References
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