Involvement of TRPC channels in CCL2-mediated neuroprotection against Tat toxicity

Honghong Yao, Fuwang Peng, Navneet Dhillon, Shannon Callen, Sirosh Bokhari, Lisa Stehno-Bittel, S. Omar Ahmad, John Q. Wang, Shilpa Buch

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Chemokine (C-C motif) ligand 2 (CCL2), also known as monocyte chemoattractant protein-1, plays a critical role in leukocyte recruitment and activation. In the present study, we identify an additional role for CCL2 that of neuroprotection against HIV-1 transactivator protein (Tat) toxicity in rat primary midbrain neurons. Furthermore, we report the involvement of transient receptor potential canonical (TRPC) channels in CCL2-mediated neuroprotection. TRPC are Ca 2+-permeable, nonselective cation channels with a variety of physiological functions. Blockage of TRPC channels resulted in suppression of both CCL2-mediated neuroprotection and intracellular Ca 2+ elevations. Parallel but distinct extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) and Akt/nuclear factor κB (NF-κB) pathways were involved in the CCL2-mediated neuroprotection. Blocking TRPC channels and specific downregulation of TRPC channels 1 and 5 resulted in suppression of CCL2-induced ERK/CREB activation but not Akt/NF-κB activation. In vivo relevance of these findings was further corroborated in wild-type and CCR2 knock-out mice. In the wild-type but not CCR2 knock-out mice, exogenous CCL2 exerted neuroprotection against intrastriatal injection of HIV-1 Tat. These findings clearly demonstrate a novel role of TRPC channels in the protection of neurons against Tat through the CCL2/CCR2 axis.

Original languageEnglish (US)
Pages (from-to)1657-1669
Number of pages13
JournalJournal of Neuroscience
Volume29
Issue number6
DOIs
StatePublished - Feb 11 2009

Keywords

  • Akt
  • CCL2
  • Ca
  • ERK
  • Midbrain neurons
  • TRPC

ASJC Scopus subject areas

  • Neuroscience(all)

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    Yao, H., Peng, F., Dhillon, N., Callen, S., Bokhari, S., Stehno-Bittel, L., Ahmad, S. O., Wang, J. Q., & Buch, S. (2009). Involvement of TRPC channels in CCL2-mediated neuroprotection against Tat toxicity. Journal of Neuroscience, 29(6), 1657-1669. https://doi.org/10.1523/JNEUROSCI.2781-08.2009