Abstract
Elevation of intracellular Ca2+ in T-lymphocytes as a consequence of T cell antigen receptor activation triggers transcriptional programs resulting in effector cytokine secretion and immune response coordination. Increase of Ca2+ concentration in T-lymphocytes follows both the Ins(1,4,5)P3-dependent release from an intracellular store and subsequent influx from extracellular milieu. Flow cytometry and the fluorescent dye Fluo-4AM have been used to demonstrate that noncompetitive NMDA receptor antagonist (+)-MK801 inhibits Ca2+ influx in T cells induced by thapsigargin. Combination of thapsigargin and (+)-MK801 with following incubation does not affect Ca2+ mobilization from intracellular stores, while decreased Ca2+ entry was observed. Overall data indicate that the ion channel blocker (+)-MK801 is able to inhibit the Ca2+ influx and confirm our suggestion about involvement of NMDA receptor in the store-operated Ca2+ entry mechanisms in human T-lymphocytes. To identify the signal transduction pathways associated with NMDA receptors in mitogen-stimulated T-lymphocytes, the cells were incubated with (+)-MK801, then activity of key phosphorylated protein kinases of MAP-activated (pERK1/2, pSAPK/JNK, p-p38), Ca2+-dependent (pCaMKII), PI3/Akt-dependent (pGSK-3β), and PKC-activated (pPKCθ) pathways were detected. The data we obtained demonstrate that (+)-MK801 treatment leads to more prominent decrease in Ras-activated protein kinases pERK1/2 and Rac-activated proteins p-p38 and pSAPK/JNK, as compared to DAG-dependent pPKCθ and Ca2+-dependent pCaMKII. These results show that NMDA receptors are mainly involved in regulation of Ras/Rac-dependent signaling in T-lymphocytes.
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Abbreviations
- APC/MHC:
-
antigen-presenting cell association with the main histocompatibility complex
- BSS:
-
buffered saline solution
- [Ca2+]i :
-
intracellular calcium concentration
- DAG:
-
diacylglycerol
- mAB:
-
monoclonal antibodies
- MAP:
-
mitogen-activated protein kinase
- NMDA:
-
N-methyl-D-aspartate
- TCR:
-
T cell antigen receptor
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Original Russian Text © L. F. Zainullina, R. S. Yamidanov, V. A. Vakhitov, Yu. V. Vakhitova, 2011, published in Biokhimiya, 2011, Vol. 76, No. 11, pp. 1517–1524.
Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM11-145, September 18, 2011.
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Zainullina, L.F., Yamidanov, R.S., Vakhitov, V.A. et al. NMDA receptors as a possible component of store-operated Ca2+ entry in human T-lymphocytes. Biochemistry Moscow 76, 1220–1226 (2011). https://doi.org/10.1134/S0006297911110034
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DOI: https://doi.org/10.1134/S0006297911110034