md-medicaldata

Authors

Srđan Stanković¹, Jovana Drljača Lero^1,2, Ivan Čapo^1,3, Bojana Andrejić Višnjić <sup>1,3

1</sup>Univerzitet u Novom Sadu, Medicinski fakultet Novi Sadbr /> ²Univerzitet u Novom Sadu, Medicinski fakultet, Katedra za farmaciju
³Univerzitet u Novom Sadu, Medicinski fakultet, Katedra za histologiju i embriologiju

 

UDK: : 616.831-006-085

The paper was received / Rad 16.03.2026.

Accepted / Rad prihvaćen: 27.03.2026.

Correspondence to

Srđan Stanković
Univerzitet u Novom Sadu,
Medicinski fakultet Novi Sad
Šekspirova 3, 21000, Novi Sad, Srbija
e-mail: 908034d25@mf.uns.ac.rs

 

 

Sažetak

 

 

Glioblastom predstavlja najagresivniji primarni tumor mozga kod odraslih i odlikuje se izrazitom invazivnošću, brzim rastom i lošom prognozom. Sve veći broj istraživanja ukazuje da ovaj tumor verovatno potiče od neuralnih progenitorskih ćelija subventrikularne zone, koje tokom tumorske transformacije zadržavaju određene molekularne i funkcionalne karakteristike svojih ćelija porekla. Među tim karakteristikama nalazi se i ekspresija receptora za gama-aminobuternu kiselinu, glavnog inhibitornog neurotransmitera u centralnom nervnom sistemu. Ovaj rad daje pregled strukture, ekspresije i funkcionalne uloge receptora tipa A i tipa B za gama-aminobuternu kiselinu u ćelijama glioblastoma, kao i njihovih sličnosti sa signalnim mehanizmima prisutnim u neuralnim progenitorskim ćelijama subventrikularne zone. Posebna pažnja posvećena je intracelularnim signalnim putevima koji se aktiviraju nakon stimulacije ovih receptora i njihovom uticaju na proliferaciju, migraciju i preživljavanje tumorskih ćelija. Takođe se razmatra terapijski potencijal farmakološke modulacije ovog sistema, uključujući antitumorske efekte diazepama posredovane receptorima za gama-aminobuternu kiselinu i mitohondrijalnim translokatorskim proteinom. Ukupno posmatrano, signalizacija posredovana receptorima za gama-aminobuternu kiselinu predstavlja važan molekularni most između porekla glioblastoma i mogućih novih terapijskih strategija.

 

Ključne reči:

glioblastom; gama-aminobuterna kiselina; subventrikularna zona

 

 

 

Abstract

 

Glioblastoma is the most aggressive primary brain tumor in adults and is characterized by extensive invasiveness, rapid growth, and poor prognosis. Increasing evidence suggests that this tumor most likely originates from neural progenitor cells located in the subventricular zone, which retain several molecular and functional features of their cells of origin during tumorigenesis. Among these features is the expression of receptors for gamma-aminobutyric acid, the principal inhibitory neurotransmitter of the central nervous system. This article provides an overview of the structure, expression patterns, and functional roles of type A and type B receptors for gamma-aminobutyric acid in glioblastoma cells, highlighting their similarities with signaling mechanisms present in neural progenitor cells of the subventricular zone. Particular attention is given to the intracellular signaling pathways activated following receptor stimulation and their influence on tumor cell proliferation, migration, and survival. In addition, the therapeutic potential of pharmacological modulation of this system is discussed, including the antitumor effects of diazepam mediated through receptors for gamma-aminobutyric acid and the mitochondrial translocator protein. Overall, signaling mediated by receptors for gamma-aminobutyric acid represents an important molecular link between glioblastoma origin and potential novel therapeutic strategies.

 

Keywords:

glioblastoma; gamma-aminobutyric acid; subventricular zone

 

 

 

 

References:

1. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-51.
2. Vleeschouwer SD. Glioblastoma. Brisbane: Codon Publications; 2017.
3. Lee JH, Lee JE, Kahng JY, et al. Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature. 2018;560(7717):243–247.
4. Loras A, Gonzalez-Bonet LG, Gutierrez-Arroyo JL, Martinez-Cadenas C, Marques-Torrejon MA. Neural Stem Cells as Potential Glioblastoma Cells of Origin. Life. 2023;13(4):905.
5. Li X, Kim HJ, Yoo J, Lee Y, Nam CH, Park J et al. Distant origin of glioblastoma recurrence: neural stem cells in the subventricular zone serve as a source of tumor reconstruction after primary resection. Mol Cancer. 2025;24(1):64.
6. Li S, Dong L, Pan Z, Yang G. Targeting the neural stem cells in subventricular zone for the treatment of glioblastoma: an update from preclinical evidence to clinical interventions. Stem Cell Res Ther. 2023;14(1):125.
7. Gupta RK, Niklasson M, Bergström T, Segerman A, Betsholtz C, Westermark B, et al. Tumor-specific migration routes of xenotransplanted human glioblastoma cells in mouse brain. Sci Rep. 2024;14:864.
8. Beiriger J, Habib A, Jovanovich N, Kodavali CV, Edwards L, Amankulor N, Zinn PO. The subventricular zone in glioblastoma: genesis, maintenance, and modeling. Front Oncol. 2022;12:790976.
9. Matarredona ER, Pastor AM. Neural stem cells of the subventricular zone as the origin of human glioblastoma stem cells: therapeutic implications. Front Oncol. 2019;9:779.
10. Alcantara Llaguno S, Sun D, Pedraza AM, Vera E, Wang Z, Burns DK et al. Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction. Nat Neurosci. 2019;22(4):545-55.
11. Whitfield BT, Huse JT. Classification of adult-type diffuse gliomas: impact of the World Health Organization 2021 update. Brain Pathol. 2022;32(4):e13062.
12. Guo X, Gu L, Li Y, Zheng Z, Chen W, Wang Y, et al. Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors. Front Oncol. 2023;13:1200815.
13. Lindberg N, Kastemar M, Olofsson T, Smits A, Uhrbom L. Oligodendrocyte progenitor cells can act as cell of origin for experimental glioma. Oncogene. 2009;28(23):2266-75.
14. Zong H, Verhaak RG, Canoll P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert Rev Mol Diagn. 2012;12(4):383-94.
15. Zamler DB, Hu J. Primitive Oligodendrocyte Precursor Cells Are Highly Susceptible to Gliomagenic Transformation. Cancer Res. 2023;83(6):807-8.
16. Ah-Pine F, Khettab M, Bedoui Y, Slama Y, Daniel M, Doray B et al. On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells. Acta Neuropathol Commun. 2023 Jun 24;11(1):104.
17. Huang Q, Chen L, Liang J, Huang Q, Sun H. Neurotransmitters: Potential Targets in Glioblastoma. Cancers (Basel). 2022 Aug 17;14(16):3970.
18. Mondal J, Huse JT. Neurotransmitter power plays: the synaptic communication nexus shaping brain cancer. Acta Neuropathol Commun. 2025;13(1):85.
19. Yool AJ, Ramesh S. Molecular Targets for Combined Therapeutic Strategies to Limit Glioblastoma Cell Migration and Invasion. Front Pharmacol. 2020;11:358.
20. Badalotti R, Dalmolin M, Malafaia O, Ribas Filho JM, Roesler R, Fernandes MAC et al. Gene Expression of GABAA Receptor Subunits and Association with Patient Survival in Glioma. Brain Sci. 2024;14(3):275.
21. Huang D, Alexander PB, Li QJ, Wang XF. GABAergic signaling beyond synapses: an emerging target for cancer therapy. Trends Cell Biol. 2023;33(5):403-12.
22. Li TJ, Jiang J, Tang YL, Liang XH. Insights into the leveraging of GABAergic signaling in cancer therapy. Cancer Med. 2023;12(13):14498-510.
23. Chen L, Huang S, Wu X, He W, Song M. Serotonin signalling in cancer: Emerging mechanisms and therapeutic opportunities. Clin Transl Med. 2024;14(7):e1750.
24. Karmakar S, Lal G. Role of serotonin receptor signaling in cancer cells and anti-tumor immunity. Theranostics. 2021;11(11):5296-312.
25. Wnorowski A, Such J, Paul RK, Wersto RP, Indig FE, Jozwiak K et al. Concurrent activation of β2-adrenergic receptor and blockage of GPR55 disrupts pro-oncogenic signaling in glioma cells. Cell Signal. 2017;36:176-88.
26. Olsen RW, Sieghart W. GABA A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology. 2009;56(1):141–8.
27. Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005;6(3):215-29.
28. Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid A receptors. Pharmacol Rev. 2008;60(3):243–60.
29. Zhu S, Noviello CM, Teng J, Walsh RM Jr, Kim JJ, Hibbs RE. Structure of a human synaptic GABA A receptor. Nature. 2018;559(7712):67–72.
30. Keramidas A, Harrison NL. The activation mechanism of α1β2γ2 GABA A receptors. J Gen Physiol. 2010;135(1):59–75.
31. Xu M, Akabas MH. Identification of channel-lining residues in the M2 membrane-spanning segment of the GABA A receptor α1 subunit. J Gen Physiol. 1996;107(2):195–205.
32. Chang Y, Weiss DS. Channel opening locks agonist onto the GABA A receptor. Nat Neurosci. 1999;2(3):219–25.
33. Miller PS, Smart TG. Binding, activation and modulation of Cys-loop receptors. Trends Pharmacol Sci. 2010;31(4):161–74.
34. Kaupmann K, Malitschek B, Schuler V, et al. GABA B-receptor subtypes assemble into functional heteromeric complexes. Nature. 1998;396:683–87.
35. Oldham WM, Hamm HE. Structural basis of function in heterotrimeric G proteins. Q Rev Biophys. 2006;39(2):117–66.
36. Sadja R, Alagem N, Reuveny E. Gating of GIRK channels: details of an intricate, membrane-delimited signaling complex. Neuron. 2003;39(1):9–12.
37. Taylor SS, Ilouz R, Zhang P, Kornev AP. Assembly of allosteric macromolecular switches. Nat Rev Mol Cell Biol. 2012;13(10):646–58.
38. Khater M, Wei Z, Xu X, et al. G protein βγ translocation to the Golgi apparatus activates MAPK via p110γ–p101 heterodimers. J Biol Chem. 2021;296:100163.
39. Peng L, Mirshahi T, Zhang H, Hirsch JP, Logothetis DE. Critical determinants of G protein gamma subunits in the Gβγ stimulation of GIRK channel activity. J Biol Chem. 2003;278(34):33495–500.
40. Vázquez-Prado J, Bracho-Valdés I, Cervantes-Villagrana RD, Reyes-Cruz G. Gβγ pathways in cell polarity and migration linked to oncogenic GPCR signaling. Mol Pharmacol. 2016;90(5):573–86.
41. Ma AD, Metjian A, Bagrodia S, Taylor S, Abrams CS. Cytoskeletal reorganization by G protein–coupled receptors is dependent on PI3Kγ, a Rac guanine nucleotide exchange factor, and Rac. Mol Cell Biol. 1998;18(8):4744–51.
42. Khodaei M, Hosseinmardi N, Sirati-Sabet M, Sahranavard S, Shahmohammadi MR, Salami S. Distinctive GABA A receptor subunit expression modulates cell specific EMT and functional responses in glioblastoma breast and ovarian cancer. Sci Rep. 2025;15(1):33695.
43. Smits A, Jin Z, Elsir T, Pedder H, Nistér M, Alafuzoff I et al. GABA-A channel subunit expression in human glioma correlates with tumor histology and clinical outcome. PLoS One. 2012;7(5):e37041.
44. Zhao Y, Xu J, Yang K, Bao L. Targeting GABA signaling in the tumor microenvironment: implications for immune cell regulation and immunotherapy resistance. Front Immunol. 2025;16:1645718.
45. Jiang X, Su L, Zhang Q, He C, Zhang Z, Yi P, Liu J. GABAB receptor complex as a potential target for tumor therapy. J Histochem Cytochem. 2012;60(4):269-79.
46. Cherry AE, Stella N. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues. Neuroscience. 2014;278:222-36.
47. Yang X, Zu Q, Wang L, Li C, Zhang L. The double role of GABAergic system in systemic tumors: an updated review. Front Oncol. 2025;15:1570380.
48. Young SZ, Taylor MM, Wu S, Ikeda-Matsuo Y, Kubera C, Bordey A. NKCC1 knockdown decreases neuron production through GABA(A)-regulated neural progenitor proliferation and delays dendrite development. J Neurosci. 2012;32(39):13630-8.
49. Xing L, Huttner WB. Neurotransmitters as Modulators of Neural Progenitor Cell Proliferation During Mammalian Neocortex Development. Front Cell Dev Biol. 2020;26;8:391.
50. Barron T, Yalçın B, Su M, Byun YG, Gavish A, Shamardani K et al. GABAergic neuron-to-glioma synapses in diffuse midline gliomas. Nature. 2025;639(8056):1060-8.
51. Blanchart A, Fernando R, Häring M, Assaife-Lopes N, Romanov RA, Andäng M et al. Endogenous GABAA receptor activity suppresses glioma growth. Oncogene. 2017;36(6):777-86.
52. Smits A, Jin Z, Elsir T, Pedder H, Nistér M, Alafuzoff I et al. GABA-A channel subunit expression in human glioma correlates with tumor histology and clinical outcome. PLoS One. 2012;7(5):e37041.
53. Shen C, Mao C, Xu C, Jin N, Zhang H, Shen DD et al. Structural basis of GABAB receptor-Gi protein coupling. Nature. 2021;594(7864):594-98.
54. Daniel PM, Filiz G, Brown DV, Christie M, Waring PM, Zhang Y et al. PI3K activation in neural stem cells drives tumorigenesis which can be ameliorated by targeting the cAMP response element binding protein. Neuro Oncol. 2018;20(10):1344-55.
55. Drljača J, Popović A, Bulajić D, Stilinović N, Vidičević Novaković S et al. Diazepam diminishes temozolomide efficacy in the treatment of U87 glioblastoma cell line. CNS Neurosci Ther. 2022;28(9):1447-57.
56. Mizan M, Yana NT, Hasan AMW, Uddin MB, Sayeed MA, Hasan A et al. Anticancer Potential of Diazepam: Pharmacological Relevance and Clinical Evidence. Journal of Phytochemical Insights. 2025;1(01):1–9.
57. Chen J, Ouyang Y, Cao L, Zhu W, Zhou Y, Zhou Y et al. Diazepam inhibits proliferation of human glioblastoma cells through triggering a G0/G1 cell cycle arrest. J Neurosurg Anesthesiol. 2013;25(3):285-91.
58. Vlodavsky E, Soustiel JF. Immunohistochemical expression of peripheral benzodiazepine receptors in human astrocytomas and its correlation with grade of malignancy, proliferation, apoptosis and survival. J Neurooncol. 2007;81(1):1-7.
59. Costa B, Da Pozzo E, Giacomelli C, Taliani S, Bendinelli S, Barresi E et al. TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance. Apoptosis. 2015;20(3):383-98.
60. Daniele S, Taliani S, Da Pozzo E, Giacomelli C, Costa B, Trincavelli ML et al. Apoptosis therapy in cancer: the first single-molecule co-activating p53 and the translocator protein in glioblastoma. Sci Rep. 2014;4:4749.
61. Habib A, Hoppe M, Beiriger J, Kodavali CV, Edwards L, Zinn PO. Letter: Glioblastoma cell of origin. Stem Cell Rev Rep. 2022;18(6):691–93.
    

PDF: 08 - Stanković S. et al MD-Medical Data 2026;18(1) 045-050.pdf