Up-Regulation of GABAergic Signal Events in Bone Marrow Lymphocytes in Childhood Acute Lymphoblastic Leukemia

10.4077/CJP.2016.BAE379

Hong-Mei Wang；Mei Feng；Yan-Li Liu；Chuan-Fei Wei；Meng-Jun Qian；Tao Li；Xu-Peng Yang；Shuang Cui；Chuan-Yong Liu；Fan Yi；Shuang-Lian Wang

gamma-aminobutyric acid (GABA) ； type-A GABA receptor (GABAAR) ； glutamic acid decarboxylase (GAD) ； lymphocyte ； childhood acute lymphoblastic leukemia (ALL)

The Chinese Journal of Physiology

59卷2期（2016 / 04 / 30）

119 - 125

英文

Gamma-aminobutyric acid (GABA) is involved in the proliferation, differentiation, and migration of several cell types including cancer cells. Whether GABA may be involved with acute lymphoblastic leukemia (ALL) is unclear. Therefore, the goal of this report was to examine if GABAergic signaling expression is altered in bone marrow lymphocytes of ALL children. RT-PCR and western blot analysis were used to examine the expression of the GABA synthetizing enzyme glutamic acid decarboxylase (GAD) isoforms (GAD65 and GAD67), and type-A GABA receptor (GABA_AR) subunits [α(1-6), β(1-3), γ(1-3), δ, ε, θ, π, and ρ(1-3)] in bone marrow lymphocytes of 19 ALL children before chemotherapy. The data obtained were compared with those in 13 age-matched non-ALL children. Immunofluorescent staining was used to examine the cellular localization of GAD. We found that GAD and GABA_AR subunits were expressed in bone marrow lymphocytes of ALL children. Moreover, RT-PCR and western blot showed that GAD and several GABA_AR subunits were significantly increased in ALL children as compared with the data of non-ALL children. Our present study reveals up-regulation of GABAergic signaling events in bone marrow lymphocytes in ALL children. However, the role of this signaling system in lymphocyte proliferation and invasion as related to the progression of ALL requires further investigation.

1. Tian, J.,Lu, Y.,Zhang, H.,Chau, C.H.,Dang, H.N.,Kaufman, D.L.(2004).γ-aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model.J. Immunol.,173,5298-5304.
   連結：
2. Alam, S.,Laughton, D.L.,Walding, A.,Wolstenholme, A.J.(2006).Human peripheral blood mononuclear cells express GABAA receptor subunits.Mol. Immunol.,43,1432-1442.
3. Andäng, M.,Hjerling-Leffler, J.,Moliner, A.,Lundgren, T.K.,Castelo-Branco, G.,Nanou, E.,Pozas, E.,Bryja, V.,Halliez, S.,Nishimaru, H.,Wilbertz, J.,Arenas, E.,Koltzenburg, M.,Charnay, P.,El Manira, A.,Ibañez, C.F.,Ernfors, P.(2008).Histone H2AXdependent GABAA receptor regulation of stem cell proliferation.Nature,451,460-464.
4. Armstrong, S.A.,Look, A.T.(2005).Molecular genetics of acute lymphoblastic leukemia.J. Clin. Oncol.,23,6306-6315.
5. Bergeret, M.,Khrestchatisky, M.,Tremblay, E.,Bernard, A.,Gregoire, A.,Chany, C.(1998).GABA modulates cytotoxicity of immunocompetent cells expressing GABAA receptor subunits.Biomed. Pharmacother.,52,214-219.
6. Bhat, R.,Axtell, R.,Mitra, A.,Miranda, M.,Lock, C.,Tsien, R.W.,Steinman, L.(2010).Inhibitory role for GABA in autoimmune inflammation.Proc. Natl. Acad. Sci. USA,107,2580-2585.
7. Birnir, B.,Korpi, E.R.(2007).The impact of sub-cellular location and intracellular neuronal proteins on properties of GABAA receptors.Curr. Pharm. Des.,13,3169-3177.
8. Bjurstöm, H.,Wang, J.,Ericsson, I.,Bengtsson, M.,Liu, Y.,Kumar-Mendu, S.,Issazadeh-Navikas, S.,Birnir, B.(2008).GABA, a natural immunomodulator of T lymphocytes.J. Neuroimmunol.,205,44-50.
9. Buddhala, C.,Hsu, C.C.,Wu, J.Y.(2006).A novel mechanism for GABA synthesis and packaging into synaptic vesicles.Neurochem. Int.,43,1364-1374.
10. Chen, C.Y.,Jia, J.H.,Zhang, M.X.,Meng, Y.S.,Kong, D.X.,Pan, X.L.,Yu, X.P.(2009).Proteomic analysis on multi-drug resistant cells HL-60/DOX of acute myeloblastic leukemia.Chinese J. Physiol.,55,9-12.
11. Dionisio, L.,José De Rosa, M.,Bouzat, C.,Esandi, M.C.(2005).An intrinsic GABAergic system in human lymphocytes.Neuropharmacology,48,115-120.
12. Feske, S.(2011).Calcium signalling in lymphocyte activation and disease.Nat. Rev. Immunol.,60,513-519.
13. Fiszman, M.,Schousboe, A.(2007).Role of calcium and kinases on the neurotrophic effect induced by γ-aminobutyric acid.J. Neurosci. Res.,7,690-702.
14. Gowda, C.,Dovat, S.(2004).Genetic targets in pediatric acute lymphoblastic leukemia.Adv. Exp. Med. Biol.,76,435-441.
15. Gowda, C.,Dovat, S.(2013).Genetic targets in pediatric acute lymphoblastic leukemia.Adv. Exp. Med. Biol.,779,327-340.
16. Hunger, S.P.,Lu, X.,Devidas, M.,Camitta, B.M.,Gaynon, P.S.,Winick, N.J.,Reaman, G.H.,Carroll, W.L.(2012).Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group.J. Clin. Oncol.,30,1663-1669.
17. Kittler, J.,Moss, S.(2003).Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition.Curr. Opin. Neurobiol.,13,341-347.
18. Korpershoek, E.,Verwest, A.M.,Ijzendoorn, Y.,Rottier, R.,Drexhage, H.A.,de Krijger, R.R.(2007).Expression of GAD67 and novel GAD67 splice variants during human fetal pancreas development: GAD67 expression in the fetal pancreas.Endocr. Pathol.,18,31-36.
19. Limon, A.,Reyes-Ruiz, J.M.,Miledi, R.(2012).Loss of functional GABAA receptors in the Alzheimer diseased brain.Proc. Natl. Acad. Sci. USA,109,10071-10076.
20. Lo Nigro, L.(2013).Biology of childhood acute lymphoblastic leukemia.J. Pediatr. Hematol. Oncol.,35,245-252.
21. Matsukawa, S.,Ueno, H.(2007).Expression of glutamate decarboxylase isoform, GAD65, in human mononuclear leucocytes: a possible implication of C-terminal end deletion by western blot and RT PCR study.J. Biochem.,142,633-638.
22. Pilas, B.,Durack, G.(1997).A flow cytometric method for measurement of intracellular chloride concentration in lymphocytes using the halide-specific probe 6-methoxy-N-(3-sulfopropyl) quinolinium (SPQ).Cytometry,28,316-322.
23. Pui, C.H.,Carroll, W.L.,Meshinchi, S.,Arceci, R.J.(2011).Biology, Risk Stratification, and Therapy of Pediatric Acute Leukemias: An Update.J. Clin. Oncol.,29,551-565.
24. Represa, A.,Ben-Ari, Y.(2005).Trophic actions of GABA on neuronal development.Trends Neurosci.,28,278-283.
25. Smits, A.,Jin, Z.,Elsir, T.,Pedder, H.,Nistér, M.,Alafuzoff, I.,Dimberg, A.,Edqvist, P.H.,Pontén, F.,Aronica, E.,Birnir, B.(2012).GABA-A channel subunit expression in human glioma correlates with tumor histology and clinical outcome.PLoS One,7,e37041.
26. Watanabe, M.,Maemura, K.,Kanbara, K.,Tamayama, T.,Hayasaki, H.(2002).GABA and GABA receptors in the central nervous system and other organs.Int. Rev. Cytol.,213,1-47.
27. Wu, H.,Jin, Y.,Buddhala, C.,Osterhaus, G.,Cohen, E.,Jin, H.,Wei, J.,Davis, K.,Obata, K.,Wu, J.Y.(2007).Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-Evidence from GAD65-knockout mice studies.Brain Res.,1154,80-83.

1. 鄒宗翰(2016)。利用分子束磊晶系統成長氮化鎵在多種基板上。交通大學照明與能源光電研究所學位論文。2016。1-120。