Platelet-Derived Growth Factor CC-Mediated Neuroprotection against HIV Tat Involves TRPC-Mediated Inactivation of GSK 3beta

Fuwang Peng, Honghong Yao, Halis Kaan Akturk, Shilpa J Buch

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Platelet-derived growth factor-CC (PDGF-CC) is the third member of the PDGF family, and has been implicated both in embryogenesis and development of the CNS. The biological function of this isoform however, remains largely unexplored in the context of HIV-associated dementia (HAD). In the present study, we demonstrate that exposure of human neuroblastoma cells SH-SY5Y to HIV transactivator protein Tat resulted in decreased intrinsic expression of PDGF-CC as evidenced by RT-PCR and western blot assays. Reciprocally, pretreatment of SH-SY5Y cells with PDGF-CC abrogated Tat-mediated neurotoxicity by mitigating apoptosis and neurite & MAP-2 loss. Using pharmacological and loss of function approaches we identified the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in PDGF-CC-mediated neuroprotection. We report herein a novel role about the involvement of transient receptor potential canonical (TRPC) channel 1 in modulation of calcium transients in PDGF-CC-mediated neuroprotection. Furthermore we also demonstrated PDGF-CC-mediated inactivation of the downstream mediator - glycogen synthase kinase 3β (GSK3β) evidenced by its phosphorylation at Ser-9. This was further validated by gain and loss of function studies using cells transfected with either the wild type or mutant GSK3β constructs. Intriguingly, pretreatment of cells with either the PI3K inhibitor or TRPC blocker resulted in failure of PDGF-CC to inactivate GSK3β, thereby suggesting the intersection of PI3K and TRPC signaling at GSK3β. Taken together our findings lead to the suggestion that PDGF-CC could be developed as a therapeutic target to reverse Tat-mediated neurotoxicity with implications for HAD.

Original languageEnglish (US)
Article numbere47572
JournalPloS one
Volume7
Issue number10
DOIs
StatePublished - Oct 15 2012

Fingerprint

platelet-derived growth factor
Platelet-Derived Growth Factor
inactivation
HIV
Glycogen Synthase Kinase 3
receptors
Phosphatidylinositol 3-Kinase
phosphatidylinositol 3-kinase
AIDS Dementia Complex
neurotoxicity
dementia
Human Immunodeficiency Virus rev Gene Products
pretreatment
cells
Transient Receptor Potential Channels
Phosphorylation
neurites
Neuroprotection
Glycogen Synthase Kinase 3 beta
Neurites

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Platelet-Derived Growth Factor CC-Mediated Neuroprotection against HIV Tat Involves TRPC-Mediated Inactivation of GSK 3beta. / Peng, Fuwang; Yao, Honghong; Akturk, Halis Kaan; Buch, Shilpa J.

In: PloS one, Vol. 7, No. 10, e47572, 15.10.2012.

Research output: Contribution to journalArticle

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