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

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 2ϩ -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 2ϩ 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.

Cocaine-mediated induction of platelet-derived growth factor: implication for increased vascular permeability

“…The secondary antibodies were alkaline phosphatase conjugated to goat anti mouse/rabbit IgG (1:5000) as described previously. 19 …”

Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling

“…Ca 2+ influx through TRPC channels appears to be a critical component of the signaling cascade that mediates growth cone guidance and survival of neurons in response to several growth factors (47,48). In particular, recent studies have shed light on the neuroprotective effect of TRPC channels in the SNpc against Tat neurotoxicity (49). Our previous studies also show the neuroprotective action of TRPC1 against in vitro cell culture models of PD (19); however, the precise mechanisms by which TRPC1 regulates neuronal survival remained poorly understood.…”

CXCL16 Orchestrates Adenosine A3Receptor and MCP-1/CCL2 Activity to Protect Neurons from Excitotoxic Cell Death in the CNS

“…Indeed, we have shown that ␣CCL2 neutralizing antibody significantly reduced CXCL16 neuroprotection. The ability of CCL2 to preserve neuronal cell death by other insults, such as HIV-1 trans-activator protein (Tat) toxicity, has been documented (Yao et al, 2009). Moreover the hypothesis that CCL2 can act as a critical intermediate factor driving neuroprotection is consistent with the findings that, in human cortical neuronal cultures, CCL2 released by astrocytes, upon RANTES stimulation, reduces the toxic effect of NMDA and Tat (Eugenin et al, 2003), and with recent data showing that astrocyte-derived CCL2 mediates the neuroprotective effect of noradrenaline against excitotoxic and OGD damages (Madrigal et al, 2009).…”