# Advances in calcium signalling research for the diagnosis and treatment of depression **Authors:** Lin Li, Mingli Yao, Jing Meng, Zhen Zhong, Nan Nan, Amir Hooman Kazemi, Jiale Guo, Chenyue Liu, Youming Jiang PMC · DOI: 10.1080/07853890.2026.2620329 · 2026-03-05 ## TL;DR This review explores how calcium signaling could help diagnose and treat depression, offering new insights beyond traditional antidepressants. ## Contribution The paper highlights novel insights into calcium signaling pathways and their potential as biomarkers and therapeutic targets for depression. ## Key findings - Calcium signaling pathways are dysregulated in depression and animal models. - Calcium signaling shows potential as a diagnostic biomarker for depression. - Emerging evidence suggests calcium signaling could guide targeted antidepressant therapies. ## Abstract The increasing global burden of depression underscores the need for novel therapeutic strategies beyond conventional antidepressants such as selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors. Given the substantial role of calcium signaling in the pathogenesis of psychiatric disorders, this review examines its critical involvement in depression to guide future research and clinical advancements. We describe the activation mechanisms of key calcium pathways, including voltage-gated channels, N-methyl-D-aspartate receptor–gated channels, endoplasmic reticulum–mediated release, and store-operated calcium entry, and summarize evidence of their dysregulation in clinical depression and animal models.Furthermore, we discuss the potential of calcium signaling as a diagnostic and prognostic biomarker, highlighting how emerging insights in this field may support the development of targeted antidepressant therapies. This review indicates that calcium signaling demonstrates potential as a diagnostic biomarker and a basis for targeted antidepressant therapies. ## Linked entities - **Diseases:** depression (MONDO:0002050) ## Full-text entities - **Genes:** Grin2b (glutamate receptor, ionotropic, NMDA2B (epsilon 2)) [NCBI Gene 14812] {aka GluN2B, GluRepsilon2, NR2B, Nmdar2b}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, CACNA1A (calcium voltage-gated channel subunit alpha1 A) [NCBI Gene 773] {aka APCA, BI, CACNL1A4, CAV2.1, DEE42, EA2}, Gria1 (glutamate ionotropic receptor AMPA type subunit 1) [NCBI Gene 50592] {aka GluA1, gluR-A}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, Camk2b (calcium/calmodulin-dependent protein kinase II, beta) [NCBI Gene 12323] {aka CaMKII}, Ahnak (AHNAK nucleoprotein) [NCBI Gene 66395] {aka DY6}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, CACNA1C (calcium voltage-gated channel subunit alpha1 C) [NCBI Gene 775] {aka CACH2, CACN2, CACNA1C-IT2, CACNL1A1, CCHL1A1, CaV1.2}, CAT (catalase) [NCBI Gene 847], SYT1 (synaptotagmin 1) [NCBI Gene 6857] {aka BAGOS, P65, SVP65, SYT}, Hspa9 (heat shock protein family A (Hsp70) member 9) [NCBI Gene 15526] {aka 74kDa, Csa, Grp75, Hsc74, Hsp74, Hsp74a}, SLC1A2 (solute carrier family 1 member 2) [NCBI Gene 6506] {aka DEE41, EAAT2, EIEE41, GLT-1, GLT1, HBGT}, Nlrp3 (NLR family, pyrin domain containing 3) [NCBI Gene 216799] {aka AGTAVPRL, AII/AVP, Cias1, FCAS, FCU, MWS}, Crh (corticotropin releasing hormone) [NCBI Gene 12918] {aka CRF, Gm1347}, ITPR2 (inositol 1,4,5-trisphosphate receptor type 2) [NCBI Gene 3709] {aka ANHD, CFAP48, INSP3R2, IP3R2}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, GSK3B (glycogen synthase kinase 3 beta) [NCBI Gene 2932], Crh (corticotropin releasing hormone) [NCBI Gene 81648] {aka CRF}, Camk4 (calcium/calmodulin-dependent protein kinase IV) [NCBI Gene 25050] {aka Ccdpk, RATCCDPK}, SLC24A3 (solute carrier family 24 member 3) [NCBI Gene 57419] {aka NCKX3}, Creb1 (cAMP responsive element binding protein 1) [NCBI Gene 12912] {aka 2310001E10Rik, 3526402H21Rik, Creb, Creb-1}, SGCG (sarcoglycan gamma) [NCBI Gene 6445] {aka 35DAG, A4, DAGA4, DMDA, DMDA1, LGMD2C}, Itpr1 (inositol 1,4,5-trisphosphate receptor 1) [NCBI Gene 16438] {aka D6Pas2, Gm10429, IP3R 1, IP3R1, InsP3R, Ip3r}, GRIN2B (glutamate ionotropic receptor NMDA type subunit 2B) [NCBI Gene 2904] {aka DEE27, EIEE27, GluN2B, MRD6, NMDAR2B, NR2B}, Itpr3 (inositol 1,4,5-triphosphate receptor 3) [NCBI Gene 16440] {aka IP3R 3, IP3R-3, Ip3r3, Itpr-3, tf}, F2 (coagulation factor II, thrombin) [NCBI Gene 2147] {aka PT, RPRGL2, THPH1}, VN1R17P (vomeronasal 1 receptor 17 pseudogene) [NCBI Gene 441931] {aka GPCR}, Trpm4 (transient receptor potential cation channel, subfamily M, member 4) [NCBI Gene 68667] {aka 1110030C19Rik, LTRPC4, LTrpC-4, TRPM4B}, NFATC1 (nuclear factor of activated T cells 1) [NCBI Gene 4772] {aka NF-ATC, NF-ATc1.2, NFAT2, NFATc}, DLG4 (discs large MAGUK scaffold protein 4) [NCBI Gene 1742] {aka MRD62, PSD95, SAP-90, SAP90}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Cacna1c (calcium channel, voltage-dependent, L type, alpha 1C subunit) [NCBI Gene 12288] {aka Cav1.2, Cchl1a1, D930026N18Rik, MBC, MELC-CC}, MROS (Melkersson-Rosenthal syndrome) [NCBI Gene 8011] {aka MRS}, STIM1 (stromal interaction molecule 1) [NCBI Gene 6786] {aka D11S4896E, GOK, IMD10, STRMK, TAM, TAM1}, RNF130 (ring finger protein 130) [NCBI Gene 55819] {aka G1RP, G1RZFP, GOLIATH, GP}, Hmgb1 (high mobility group box 1) [NCBI Gene 15289] {aka HMG-1, Hmg1, SBP-1, p30}, CACNA1G (calcium voltage-gated channel subunit alpha1 G) [NCBI Gene 8913] {aka Ca(V)T.1, Cav3.1, NBR13, SCA42, SCA42ND}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, Crtc1 (CREB regulated transcription coactivator 1) [NCBI Gene 382056] {aka Mect1, TORC-1, TORC1, mKIAA0616}, Slc6a4 (solute carrier family 6 (neurotransmitter transporter, serotonin), member 4) [NCBI Gene 15567] {aka 5-HTT, Htt, Sert}, Sik1 (salt inducible kinase 1) [NCBI Gene 17691] {aka Hrt-20, Msk, Sik, Sik-1, Snf1lk}, S100a10 (S100 calcium binding protein A10 (calpactin)) [NCBI Gene 20194] {aka 42C, CAL12, CLP11, Cal1l, p10, p11}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, MCU (mitochondrial calcium uniporter) [NCBI Gene 90550] {aka C10orf42, CCDC109A, HsMCU}, S100b (S100 protein, beta polypeptide, neural) [NCBI Gene 20203] {aka Bpb}, GRIN1 (glutamate ionotropic receptor NMDA type subunit 1) [NCBI Gene 2902] {aka DEE101, GluN1, MRD8, NDHMSD, NDHMSR, NMD-R1}, ITPR3 (inositol 1,4,5-trisphosphate receptor type 3) [NCBI Gene 3710] {aka CMT1J, IMD132, IMD133, IP3R, IP3R-3, IP3R3}, ORAI1 (ORAI calcium release-activated calcium modulator 1) [NCBI Gene 84876] {aka CRACM1, IMD9, ORAT1, TAM2, TMEM142A}, ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) [NCBI Gene 488] {aka ATP2B, DAR, DD, RHABDO2, SERCA2}, C3 (complement C3) [NCBI Gene 718] {aka AHUS5, ARMD9, ASP, C3a, C3b, CPAMD1}, SYN1 (synapsin I) [NCBI Gene 6853] {aka EPILX, EPILX1, MRX50, SYN1a, SYN1b, SYNI}, EEF2K (eukaryotic elongation factor 2 kinase) [NCBI Gene 29904] {aka CaMKIII, HSU93850, eEF-2K}, Cat (catalase) [NCBI Gene 24248] {aka CS1, Cas1, Cat01, Catl, Cs-1}, Calb1 (calbindin 1) [NCBI Gene 12307] {aka Brain-2, CB, Calb, Calb-1}, PRKCE (protein kinase C epsilon) [NCBI Gene 5581] {aka PKCE, nPKC-epsilon}, Nr3c1 (nuclear receptor subfamily 3, group C, member 1) [NCBI Gene 14815] {aka GR, Grl-1, Grl1}, HSPG2 (heparan sulfate proteoglycan 2) [NCBI Gene 3339] {aka HSPG, PLC, PRCAN, SJA, SJS, SJS1}, Hspg2 (perlecan (heparan sulfate proteoglycan 2)) [NCBI Gene 15530] {aka HSPG, Pcn, Plc, per} - **Diseases:** CUMS (MESH:D000079225), LTD (MESH:D000088562), spine (MESH:D016135), hypertension (MESH:D006973), Hyperactivation of (MESH:D011504), cardiovascular disease (MESH:D002318), insulin resistance (MESH:D007333), Depression (MESH:D003866), OCD (MESH:D009771), chronic pain (MESH:D059350), Calcium (MESH:D002128), neuronal excitotoxicity (MESH:D009410), MAMs (MESH:D015433), Social Defeat (OMIM:300082), cognitive deficits (MESH:D003072), apoptosis (MESH:D065703), volume loss (MESH:D016388), inflammation (MESH:D007249), mitochondrial dysfunction (MESH:D028361), pain (MESH:D010146), anhedonia (MESH:D059445), hypothalamic-pituitary-adrenal (HPA) axis dysfunction (MESH:D007027), mental disorder (MESH:D001523), neurotoxicity (MESH:D020258), central nervous system dysfunction (MESH:D002493), schizophrenia (MESH:D012559), Neuroinflammation (MESH:D000090862), spine atrophy (MESH:D001284), anxiety (MESH:D001007), BD (MESH:D001528), HPA axis (MESH:D007029), mood disorders (MESH:D019964), MDD (MESH:D000069279), CRS (MESH:D013313), hyperactivity (MESH:D006948), Major Depressive Disorder (MESH:D003865) - **Chemicals:** CP (-), sodium (MESH:D012964), silica (MESH:D012822), potassium (MESH:D011188), SSB2 (MESH:C025759), cocaine (MESH:D003042), GSH (MESH:D005978), Fura-2 AM (MESH:C049925), Ketamine (MESH:D007649), ATP (MESH:D000255), Ro-25-6981 (MESH:C109643), LPS (MESH:D008070), lipid (MESH:D008055), sucrose (MESH:D013395), alcohol (MESH:D000438), verapamil (MESH:D014700), dopamine (MESH:D004298), Calcium (MESH:D002118), ROS (MESH:D017382), saponin (MESH:D012503), 5-HT (MESH:D012701), flavonoids (MESH:D005419), diltiazem (MESH:D004110), PI (MESH:D010716), Cortisol (MESH:D006854), Ginsenoside Rg1 (MESH:C035054), nicardipine (MESH:D009529), DA (MESH:C025953), YM58483 (MESH:C476308), Quercetin (MESH:D011794), 5-Bromo-2'-deoxyuridine (MESH:D001973), memantine (MESH:D008559), AC (MESH:D000186), paroxetine (MESH:D017374), corticosterone (MESH:D003345), Kaempferol (MESH:C006552), IP3 (MESH:D015544), Esketamine (MESH:C000629870), Lithium (MESH:D008094), iron (MESH:D007501), Fura-2 (MESH:D016257), glutamate (MESH:D018698), NE (MESH:D009638), JuA (MESH:C087808), GABA (MESH:D005680), di-hydropyridines (MESH:D004095), glycine (MESH:D005998), borneol (MESH:C022871), HA (MESH:D006820) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Rodentia (rodent, order) [taxon 9989], Mus musculus (house mouse, species) [taxon 10090], Panax ginseng (Asiatic ginseng, species) [taxon 4054] - **Mutations:** rs11832738, serine/threonine, rs1006737 ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12973800/full.md --- Source: https://tomesphere.com/paper/PMC12973800