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 language | English (US) |
---|---|
Pages (from-to) | 1657-1669 |
Number of pages | 13 |
Journal | Journal of Neuroscience |
Volume | 29 |
Issue number | 6 |
DOIs | |
State | Published - Feb 11 2009 |
Fingerprint
Keywords
- Akt
- CCL2
- Ca
- ERK
- Midbrain neurons
- TRPC
ASJC Scopus subject areas
- Neuroscience(all)
Cite this
Involvement of TRPC channels in CCL2-mediated neuroprotection against Tat toxicity. / Yao, Honghong; Peng, Fuwang; Dhillon, Navneet; Callen, Shannon; Bokhari, Sirosh; Stehno-Bittel, Lisa; Ahmad, S. Omar; Wang, John Q.; Buch, Shilpa.
In: Journal of Neuroscience, Vol. 29, No. 6, 11.02.2009, p. 1657-1669.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Involvement of TRPC channels in CCL2-mediated neuroprotection against Tat toxicity
AU - Yao, Honghong
AU - Peng, Fuwang
AU - Dhillon, Navneet
AU - Callen, Shannon
AU - Bokhari, Sirosh
AU - Stehno-Bittel, Lisa
AU - Ahmad, S. Omar
AU - Wang, John Q.
AU - Buch, Shilpa
PY - 2009/2/11
Y1 - 2009/2/11
N2 - 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.
AB - 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.
KW - Akt
KW - CCL2
KW - Ca
KW - ERK
KW - Midbrain neurons
KW - TRPC
UR - http://www.scopus.com/inward/record.url?scp=60749137640&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=60749137640&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2781-08.2009
DO - 10.1523/JNEUROSCI.2781-08.2009
M3 - Article
C2 - 19211873
AN - SCOPUS:60749137640
VL - 29
SP - 1657
EP - 1669
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 6
ER -