Chapter 4 P2Y receptors in the nervous system: Molecular studies of a P2Y2 receptor subtype from NG108–15 neuroblastoma x glioma hybrid cells

Weisman, Gary A.; Garrad, Richard C.; Erb, Laurie; Santos‐Berríos, Cynthia; González, Fernando

doi:10.1016/s0079-6123(08)63544-x

Cited by 15 publications

(19 citation statements)

References 68 publications

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“…Expression of P2Y 2 receptor mRNA has been detected in human skeletal muscle, heart, brain, spleen, lymphocytes, macrophages, bone marrow, and lung, with lower expression levels detected in liver, stomach, and pancreas . Functional P2Y 2 receptors are expressed in epithelial, smooth muscle, and endothelial cells and in leukocytes, cardiomyocytes, osteoblasts, and cells derived from the peripheral and central nervous system, including Schwann cells, rat cortical neurons, oligodendrocytes, dorsal horn and cortical astrocytes, immortalized astrocytes, astrocytoma cells, and NG108-15 neuroblastoma ϫ glioma hybrid cells (Bowler et al, 1995;Ho et al, 1995;Kirischuk et al, 1995;Rice et al, 1995;Berti-Mattera et al, 1996;Kim et al, 1996;Kunapuli and Daniel, 1998;Weisman et al, 1999;Pillois et al, 2002;Seye et al, 2002;Gendron et al, 2003;Kumari et al, 2003).…”

Section: B P2ymentioning

confidence: 99%

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

et al. 2006

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Section: B P2ymentioning

confidence: 99%

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

et al. 2006

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“…Seven P2X receptors have been cloned and characterized as ligand-gated ion channels, including P2X 1 , P2X 2 , P2X 3 , P2X 4 , P2X 5 , P2X 6 , and P2X 7 receptors [52]. Activation of P2 receptors in neurons and glia under normal and pathological conditions regulates pro-inflammatory responses, ion transport, neurotransmission and cell apoptosis, proliferation, and migration [42–44, 52–54]. Therefore, P2 receptors in the CNS represent potential targets for pharmaceutical approaches to treat neurological disorders.…”

Section: The P2 Receptor Familymentioning

confidence: 99%

P2Y2 Nucleotide Receptor-Mediated Responses in Brain Cells

et al. 2010

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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 Gq protein-coupled P2Y2 nucleotide receptor subtype (P2Y2R) leading to pro-inflammatory responses that can protect neurons from injury, including the stimulation and recruitment of glial cells. P2Y2R 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 P2Y2R that promotes Src binding and transactivation of EGFR, a pathway that regulates the proliferation of cortical astrocytes. Other studies indicate that P2Y2R activation increases astrocyte migration. P2Y2R activation by UTP increases the expression in astrocytes of αVβ3/5 integrins that bind directly to the P2Y2R via an Arg-Gly-Asp (RGD) motif in the first extracellular loop of the P2Y2R, an interaction required for Go and G12 protein-dependent astrocyte migration. In rat primary cortical neurons (rPCNs) P2Y2R 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 (Aβ1-42), a contributor to AD, increases nucleotide release from astrocytes, which would serve to activate upregulated P2Y2Rs in neurons. Data with rPCNs suggest that P2Y2R 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 P2Y2Rs in rPCNs increases the phosphorylation of cofilin, a cytoskeletal protein that stabilizes neurite outgrowths. Thus, activation of pro-inflammatory P2Y2Rs in glial cells can promote neuroprotective responses, suggesting that P2Y2Rs represent a novel pharmacological target in neurodegenerative and other pro-inflammatory diseases.

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“…P2Y 2 -receptor fragments containing this motif have been shown to bind αvβ 3 -integrin. Hence, the integrin binding sites present on P2Y-receptors may play a functional role during cell differentiation or tissue injury (Weisman et al 1999). Site-directed mutagenesis experiments also indicate that the intracellular C-terminus of the P2Y 2 -receptor is involved in the agonist-induced receptor desensitisation as well as in the induced receptor sequestration (Garrad et al 1998).…”

Section: Multiple Signal Transduction Pathwaysmentioning

confidence: 99%

Molecular pharmacology of P2Y-receptors

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Wetter

2000

Naunyn-Schmied Arch Pharmacol

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Membrane-bound P2-receptors mediate the actions of extracellular nucleotides in cell-to-cell signalling. P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled receptors. So far, the P2Y family is composed of eight cloned and functionally defined subtypes. Five of them (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11) are present in human tissues. The P2Y3-, p2y8- and tp2y-receptors may be species orthologues. The principal physiological agonists of the cloned human P2Y-receptors are ADP (P2Y1), UTP/ATP (P2Y2), UTP (P2Y4), UDP (P2Y6) and ATP (P2Y11). The rat P2Y4-receptor is activated by both UTP and ATP. Specific patterns of polar amino acid residues in the exofacial portions of transmembrane domains (TMs) 6 and 7 of the P2Y-receptors may account for the ligand specificity of the subtypes. Suramin acts as an antagonist at most P2Y-receptors with the exception of P2Y4- and tp2y-receptors. PPADS has been shown to block P2Y1-, the human P2Y4- and P2Y6-receptors. The nucleotide analogue 2'-deoxy-N6-methyladenosine-3',5'-bisphosphate (MRS 2179), in contrast, seems to be a potent and selective antagonist at the P2Y1-receptor. All cloned and functionally expressed P2Y-receptors are able to couple to phospholipase C. The P2Y11-receptor mediates in addition a stimulation of adenylate cyclase and the tp2y-receptor an inhibition of this signal transduction pathway. Other functionally defined subtypes, e.g., the receptor mediating an inhibition of adenylate cyclase in blood platelets, are not yet cloned. The distribution of P2Y1 mRNA is widespread. The receptor plays a crucial role in blood platelet aggregation and mediates the adenine nucleotide-induced release of the endothelium-derived relaxing factor nitric oxide. P2Y1-receptors may also be involved in the modulation of neuro-neural signalling transmission. P2Y2 transcripts are abundantly distributed. One important example for its functional role is the control of chloride ion fluxes in airway epithelia. The P2Y4-receptor is highly expressed in the placenta. The distribution of the P2Y6-receptor is widespread including heart, blood vessels and brain. The P2Y11-receptor may play a role in the differentiation of immunocytes.

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Chapter 4 P2Y receptors in the nervous system: Molecular studies of a P2Y2 receptor subtype from NG108–15 neuroblastoma x glioma hybrid cells

Cited by 15 publications

References 68 publications

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

P2Y2 Nucleotide Receptor-Mediated Responses in Brain Cells

Molecular pharmacology of P2Y-receptors

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