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The Journal of Neuroscience, February 11, 2009, 29(6):1657-1669; doi:10.1523/JNEUROSCI.2781-08.2009

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Neurobiology of Disease
Involvement of TRPC Channels in CCL2-Mediated Neuroprotection against Tat Toxicity

Honghong Yao,¹ Fuwang Peng,¹ Navneet Dhillon,¹ Shannon Callen,¹ Sirosh Bokhari,¹ Lisa Stehno-Bittel,^1,2 S. Omar Ahmad,³ John Q. Wang,⁴ and Shilpa Buch¹

Departments of ¹Molecular and Integrative Physiology, ²Physical Therapy and Rehabilitation Science, and ³Occupational Therapy and Therapeutic Science, University of Kansas Medical Center, Kansas City, Kansas 66160, and ⁴Department of Basic Medical Science, University of Missouri–Kansas City School of Medicine, Kansas City, Missouri 64108

Correspondence should be addressed to Dr. Shilpa Buch, Department of Molecular and Integrative Physiology, 5000 Wahl Hall East, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. Email: sbuch{at}kumc.edu

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 Ca²⁺-permeable, nonselective cation channels with a variety of physiological functions. Blockage of TRPC channels resulted in suppression of both CCL2-mediated neuroprotection and intracellular Ca²⁺ elevations. Parallel but distinct extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB) and Akt/nuclear factor B (NF-B) 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-B 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.

Key words: CCL2; TRPC; midbrain neurons; Ca²⁺; ERK; Akt

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Received June 18, 2008; revised Oct. 31, 2008; accepted Dec. 24, 2008.

Correspondence should be addressed to Dr. Shilpa Buch, Department of Molecular and Integrative Physiology, 5000 Wahl Hall East, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. Email: sbuch{at}kumc.edu

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