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Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLCγ, PKC, and PI3K/Akt pathways during colitis.
J Neuroinflammation. 2015 Aug 20; 12:151.JN

Abstract

BACKGROUND

Spinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity. The release of brain-derived neurotrophic factor (BDNF) from the primary afferent neurons to the spinal cord contributes to spinal neuronal plasticity and increases neuronal activity and synaptic efficacy. The N-Methyl-D-aspartic acid (NMDA) receptor possesses ion channel properties, and its activity is modulated by phosphorylation of its subunits including the NMDA receptor 1 (NR1).

METHODS

Colonic inflammation was induced by a single dose of intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS). NR1 phosphorylation by BDNF in vivo and in culture was examined by western blot and immunohistochemistry. Signal transduction was studied by direct examination and use of specific inhibitors.

RESULTS

During colitis, the level of NR1 phospho-Ser(896) was increased in the dorsal horn region of the L1 and S1 spinal cord; this increase was attenuated by injection of BDNF neutralizing antibody to colitic animals (36 μg/kg, intravenous (i.v.)) and was also reduced in BDNF(+/-) rat treated with TNBS. Signal transduction examination showed that the extracellular signal-regulated kinase (ERK) activation was not involved in BDNF-induced NR1 phosphorylation. In contrast, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediated BDNF-induced NR1 phosphorylation in vivo and in culture; this is an additional pathway to the phospholipase C-gamma (PLCγ) and the protein kinase C (PKC) that was widely considered to phosphorylate NR1 at Ser(896). In spinal cord culture, the inhibitors to PLC (U73122), PKC (bisindolylmaleimide I), and PI3K (LY294002), but not MEK (PD98059) blocked BDNF-induced NR1 phosphorylation. In animals with colitis, treatment with LY294002 (50 μg/kg, i.v.) blocked the Akt activity as well as NR1 phosphorylation at Ser(896) in the spinal cord.

CONCLUSION

BDNF participates in colitis-induced spinal central sensitization by up-regulating NR1 phosphorylation at Ser(896). The PI3K/Akt pathway, in addition to PLCγ and PKC, mediates BDNF action in the spinal cord during colitis.

Authors+Show Affiliations

Department of Physiology and Biophysics, Internal Medicine Gastroenterology, Virginia Commonwealth University School of Medicine, 1220 East Broad Street MMRB 5046, Richmond, VA, 23298-0551, USA. mliu3@vcu.edu.Department of Physiology and Biophysics, Internal Medicine Gastroenterology, Virginia Commonwealth University School of Medicine, 1220 East Broad Street MMRB 5046, Richmond, VA, 23298-0551, USA. jkay4223@gmail.com.Department of Physiology and Biophysics, Internal Medicine Gastroenterology, Virginia Commonwealth University School of Medicine, 1220 East Broad Street MMRB 5046, Richmond, VA, 23298-0551, USA. sshen@vcu.edu.Department of Physiology and Biophysics, Internal Medicine Gastroenterology, Virginia Commonwealth University School of Medicine, 1220 East Broad Street MMRB 5046, Richmond, VA, 23298-0551, USA. lqiao2@vcu.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26289587

Citation

Liu, Miao, et al. "Endogenous BDNF Augments NMDA Receptor Phosphorylation in the Spinal Cord Via PLCγ, PKC, and PI3K/Akt Pathways During Colitis." Journal of Neuroinflammation, vol. 12, 2015, p. 151.
Liu M, Kay JC, Shen S, et al. Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLCγ, PKC, and PI3K/Akt pathways during colitis. J Neuroinflammation. 2015;12:151.
Liu, M., Kay, J. C., Shen, S., & Qiao, L. Y. (2015). Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLCγ, PKC, and PI3K/Akt pathways during colitis. Journal of Neuroinflammation, 12, 151. https://doi.org/10.1186/s12974-015-0371-z
Liu M, et al. Endogenous BDNF Augments NMDA Receptor Phosphorylation in the Spinal Cord Via PLCγ, PKC, and PI3K/Akt Pathways During Colitis. J Neuroinflammation. 2015 Aug 20;12:151. PubMed PMID: 26289587.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endogenous BDNF augments NMDA receptor phosphorylation in the spinal cord via PLCγ, PKC, and PI3K/Akt pathways during colitis. AU - Liu,Miao, AU - Kay,Jarren C, AU - Shen,Shanwei, AU - Qiao,Li-Ya, Y1 - 2015/08/20/ PY - 2015/04/13/received PY - 2015/08/06/accepted PY - 2015/8/21/entrez PY - 2015/8/21/pubmed PY - 2016/6/22/medline SP - 151 EP - 151 JF - Journal of neuroinflammation JO - J Neuroinflammation VL - 12 N2 - BACKGROUND: Spinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity. The release of brain-derived neurotrophic factor (BDNF) from the primary afferent neurons to the spinal cord contributes to spinal neuronal plasticity and increases neuronal activity and synaptic efficacy. The N-Methyl-D-aspartic acid (NMDA) receptor possesses ion channel properties, and its activity is modulated by phosphorylation of its subunits including the NMDA receptor 1 (NR1). METHODS: Colonic inflammation was induced by a single dose of intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS). NR1 phosphorylation by BDNF in vivo and in culture was examined by western blot and immunohistochemistry. Signal transduction was studied by direct examination and use of specific inhibitors. RESULTS: During colitis, the level of NR1 phospho-Ser(896) was increased in the dorsal horn region of the L1 and S1 spinal cord; this increase was attenuated by injection of BDNF neutralizing antibody to colitic animals (36 μg/kg, intravenous (i.v.)) and was also reduced in BDNF(+/-) rat treated with TNBS. Signal transduction examination showed that the extracellular signal-regulated kinase (ERK) activation was not involved in BDNF-induced NR1 phosphorylation. In contrast, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediated BDNF-induced NR1 phosphorylation in vivo and in culture; this is an additional pathway to the phospholipase C-gamma (PLCγ) and the protein kinase C (PKC) that was widely considered to phosphorylate NR1 at Ser(896). In spinal cord culture, the inhibitors to PLC (U73122), PKC (bisindolylmaleimide I), and PI3K (LY294002), but not MEK (PD98059) blocked BDNF-induced NR1 phosphorylation. In animals with colitis, treatment with LY294002 (50 μg/kg, i.v.) blocked the Akt activity as well as NR1 phosphorylation at Ser(896) in the spinal cord. CONCLUSION: BDNF participates in colitis-induced spinal central sensitization by up-regulating NR1 phosphorylation at Ser(896). The PI3K/Akt pathway, in addition to PLCγ and PKC, mediates BDNF action in the spinal cord during colitis. SN - 1742-2094 UR - https://www.unboundmedicine.com/medline/citation/26289587/Endogenous_BDNF_augments_NMDA_receptor_phosphorylation_in_the_spinal_cord_via_PLCγ_PKC_and_PI3K/Akt_pathways_during_colitis_ L2 - https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-015-0371-z DB - PRIME DP - Unbound Medicine ER -