title: Platelet-derived growth factor-BB restores human immunodeficiency virus Tat-cocaine-mediated impairment of neurogenesis: role of TRPC1 channels.
abstract: Platelet-derived growth factor-BB (PDGF-BB) has been reported to provide tropic support for neurons in the CNS. However, whether PDGF-BB regulates neurogenesis, especially in the context of HIV-associated neurological disorder and drug abuse, remains essentially unknown. In this study, we demonstrate that pretreatment of rat hippocampal neuronal progenitor cells (NPCs) with PDGF-BB restored proliferation that had been impaired by HIV Tat-cocaine via the cognate receptors. We identify the essential role of transient receptor potential canonical (TRPC) channels in PDGF-BB-mediated proliferation. Parallel but distinct ERK/CREB, phosphatidylinositol 3-kinase/Akt signaling pathways with downstream activation of mammalian target of rapamycin (mTOR)/eukaryotic translation initiation factor 4E-binding protein (4E-BP)-p70S6K and nuclear factor-κB were critical for proliferation. Blocking TRPC1 channel suppressed PDGF-mediated proliferation as well as PDGF-BB-induced ERK/CREB and mTOR/4E-BP-p70S6K activation, thereby underscoring its role in this process. In vivo relevance of these findings was further corroborated in Tat transgenic mice wherein hippocampal injection of recombinant AAV2-PDGF-B restored impaired NPC proliferation that was induced by Tat-cocaine. Together, these data underpin the role of TRPC1 channel as a novel target that regulates cell proliferation mediated by PDGF-BB with implications for therapeutic intervention for reversal of impaired neurogenesis inflicted by Tat and cocaine.
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. hyao@unmc.edu
authors: Honghong
authors: H
authors: Yao
authors: Ming
authors: M
authors: Duan
authors: Lu
authors: L
authors: Yang
authors: Shilpa
authors: S
authors: Buch
mesh_terms: D000818:Animals; D000077214:Becaplermin; D049109:Cell Proliferation / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000494:pharmacology*
chemical_list: D018765:Dopamine Uptake Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D050052:TRPC Cation Channels; D054322:tat Gene Products, Human Immunodeficiency Virus; C096351:transient receptor potential cation channel, subfamily C, member 1; D000077214:Becaplermin; D003042:Cocaine