Involvement of TRPC channels in CCL2-mediated neuroprotection against tat toxicity.
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 kappaB (NF-kappaB) 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-kappaB 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.
Yao
Honghong
H
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Peng
Fuwang
F
Dhillon
Navneet
N
Callen
Shannon
S
Bokhari
Sirosh
S
Stehno-Bittel
Lisa
L
Ahmad
S Omar
SO
Wang
John Q
JQ
Buch
Shilpa
S
D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000502:physiology*; D005260:Female; D007276:Injections, Intraventricular; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D050052:TRPC Cation Channels / Q000502:physiology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*
C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D050052:TRPC Cation Channels; C503500:Trpc5 protein, rat; C492145:Trpc6 protein, rat; D054322:tat Gene Products, Human Immunodeficiency Virus; C096351:transient receptor potential cation channel, subfamily C, member 1