NDLI: P2Y$_{2}$ Nucleotide Receptor-Mediated Responses in Brain Cells

Content Provider	Springer Nature Link
Author	Peterson, Troy S. Camden, Jean M. Wang, Yanfang Seye, Cheikh I. Wood, W. G. Sun, Grace Y. Erb, Laurie Petris, Michael J. Weisman, Gary A.
Copyright Year	2010
Abstract	Acute inflammation is important for tissue repair; however, chronic inflammation contributes to neurodegeneration in Alzheimer's disease (AD) and occurs when glial cells undergo prolonged activation. In the brain, stress or damage causes the release of nucleotides and activation of the G$_{q}$ protein-coupled P2Y$_{2}$ nucleotide receptor subtype (P2Y$_{2}$R) leading to pro-inflammatory responses that can protect neurons from injury, including the stimulation and recruitment of glial cells. P2Y$_{2}$R activation induces the phosphorylation of the epidermal growth factor receptor (EGFR), a response dependent upon the presence of a SH3 binding domain in the intracellular C terminus of the P2Y$_{2}$R that promotes Src binding and transactivation of EGFR, a pathway that regulates the proliferation of cortical astrocytes. Other studies indicate that P2Y$_{2}$R activation increases astrocyte migration. P2Y$_{2}$R activation by UTP increases the expression in astrocytes of α$_{V}$β$_{3/5}$ integrins that bind directly to the P2Y$_{2}$R via an Arg-Gly-Asp (RGD) motif in the first extracellular loop of the P2Y$_{2}$R, an interaction required for G$_{o}$ and G$_{12}$ protein-dependent astrocyte migration. In rat primary cortical neurons (rPCNs) P2Y$_{2}$R expression is increased by stimulation with interleukin-1β (IL-1β), a pro-inflammatory cytokine whose levels are elevated in AD, in part due to nucleotide-stimulated release from glial cells. Other results indicate that oligomeric β-amyloid peptide (Aβ$_{1-42}$), a contributor to AD, increases nucleotide release from astrocytes, which would serve to activate upregulated P2Y$_{2}$Rs in neurons. Data with rPCNs suggest that P2Y$_{2}$R upregulation by IL-1β and subsequent activation by UTP are neuroprotective, since this increases the non-amyloidogenic cleavage of amyloid precursor protein. Furthermore, activation of IL-1β-upregulated P2Y$_{2}$Rs in rPCNs increases the phosphorylation of cofilin, a cytoskeletal protein that stabilizes neurite outgrowths. Thus, activation of pro-inflammatory P2Y$_{2}$Rs in glial cells can promote neuroprotective responses, suggesting that P2Y$_{2}$Rs represent a novel pharmacological target in neurodegenerative and other pro-inflammatory diseases.
Starting Page	356
Ending Page	366
Page Count	11
File Format	PDF
ISSN	08937648
Journal	Molecular Neurobiology
Volume Number	41
Issue Number	2-3
e-ISSN	15591182
Language	English
Publisher	Humana Press Inc
Publisher Date	2010-04-13
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Neurons Neurodegeneration Astrocytes Growth factor receptors Inflammation P2Y$_{2}$ receptors Cofilin Nucleotides Proliferation RGD motif SH3 binding domain Integrins Neurology Cell Biology Neurobiology Neurosciences
Content Type	Text
Resource Type	Article
Subject	Neurology Cellular and Molecular Neuroscience

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