P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation

Coutinho‐Silva, Robson; Stahl, Lynn; Cheung, Kwok-Kuen; Campos, Nathalia Enes de; Souza, Carolina de; Ojcius, David M.; Burnstock, Geoffrey

doi:10.1152/ajpgi.00211.2004

Cited by 111 publications

(121 citation statements)

References 63 publications

(113 reference statements)

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“…In addition, P2Y 1 , P2Y 2 , and P2X 1-7 receptor proteins are expressed in these cells. Functional studies on cell proliferation and apoptosis using selective agonists and antagonists suggested involvement of P2X 7 , P2Y 1 , P2Y 2 , and P2Y 4 receptors but their role in secretion awaits further study [31].…”

Section: Mucosal Epithelial Cell Lines and Ion Transportmentioning

confidence: 99%

Purinergic receptors and gastrointestinal secretomotor function

Christofi

2008

Purinergic Signalling

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Secretomotor reflexes in the gastrointestinal (GI) tract are important in the lubrication and movement of digested products, absorption of nutrients, or the diarrhea that occurs in diseases to flush out unwanted microbes. Mechanical or chemical stimulation of mucosal sensory enterochromaffin (EC) cells triggers release of serotonin (5-HT) (among other mediators) and initiates local reflexes by activating intrinsic primary afferent neurons of the submucous plexus. Signals are conveyed to interneurons or secretomotor neurons to stimulate chloride and fluid secretion. Inputs from myenteric neurons modulate secretory rates and reflexes, and special neural circuits exist to coordinate secretion with motility. Cellular components of secretomotor reflexes variably express purinergic receptors for adenosine (A1, A2a, A2b, or A3 receptors) or the nucleotides adenosine 5′-triphosphate (ATP), adenosine diphosphate (ADP), uridine 5′-triphosphate (UTP), or uridine diphosphate (UDP) (P2X 1-7 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 12 receptors). This review focuses on the emerging concepts in our understanding of purinergic regulation at these receptors, and in particular of mechanosensory reflexes. Purinergic inhibitory (A 1 , A 3 , P2Y 12 ) or excitatory (A 2 , P2Y 1 ) receptors modulate mechanosensitive 5-HT release. Excitatory (P2Y 1 , other P2Y, P2X) or inhibitory (A 1 , A 3 ) receptors are involved in mechanically evoked secretory reflexes or "neurogenic diarrhea." Distinct neural (pre-or postsynaptic) and non-neural distribution profiles of P2X 2 , P2X 3 , P2X 5 , P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , or P2Y 12 receptors, and for some their effects on neurotransmission, suggests their role in GI secretomotor function. Luminal A 2b , P2Y 2 , P2Y 4 , and P2Y 6 receptors are involved in fluid and Cl -, HCO 3 -, K + , or mucin secretion. Abnormal receptor expression in GI diseases may be of clinical relevance. Adenosine A 2a or A 3 receptors are emerging as therapeutic targets in inflammatory bowel diseases (IBD) and gastroprotection; they can also prevent purinergic receptor abnormalities and diarrhea. Purines are emerging as fundamental regulators of enteric secretomotor reflexes in health and disease.

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Section: Mucosal Epithelial Cell Lines and Ion Transportmentioning

confidence: 99%

Purinergic receptors and gastrointestinal secretomotor function

Christofi

2008

Purinergic Signalling

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“…P2 receptors, which are comprised of P2X (ionotropic) and P2Y (metabotropic, G-protein-coupled) subtypes, respond to a variety of nucleotide agonists. The role of P2 receptors, particularly P2X receptors, in apoptosis has been demonstrated in both non-neuronal and neuronal cells, including most prominently the P2X 7 receptor in initiating spinal neuron apoptosis (Franke et al, 2004;Wang et al, 2004;Coutinho-Silva et al, 2005). In contrast, the role of P2Y receptors in neuronal apoptosis remains mostly unexplored.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Apoptosis by P2Y₂Receptor Activation: Novel Pathways for Neuronal Survival

Arthur

Georgi²,

Akassoglou³

et al. 2006

J. Neurosci.

102

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Cell survival is an essential function in the development and maintenance of the nervous system. We demonstrate here a previously unappreciated role for extracellular nucleotide signaling through the P2Y 2 receptor in the survival of neurons: PC12 (pheochromocytoma 12) cells and dorsal root ganglion neurons are protected from serum starvation-induced apoptosis by ATP, UTP, and ATP␥S, an effect mediated via P2Y 2 receptors, as demonstrated by small interfering RNA and genetic knock-out models. This protection occurs independently of neurophin signaling but requires Src activation of ERK (extracellular signal-regulated kinase) and Akt. Moreover, ATP␥S and NGF act synergistically to enhance neuronal survival through enhanced TrkA signaling. The results, which define a novel mechanism for inhibition of apoptosis, implicate parallel, interacting systems-extracellular nucleotides/P2Y 2 receptors and neurotrophin/TrkA-to sustain neuronal survival.

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“…P2Y receptors have been linked to either induction/suppression of apoptosis or hypoxic stress and proliferation (Kim et al 2003a, Yitzhaki et al 2005, Coutinho-Silva et al 2005.…”

mentioning

confidence: 99%

Agonists and Antagonists for P2 Receptors

Jacobson

Costanzi

Joshi

et al. 2006

Novartis Foundation Symposia

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Recent work has identified nucleotide agonists selective for P2Y 1 , P2Y 2 and P2Y 6 receptors and nucleotide antagonists selective for P2Y 1 , P2Y 12 and P2X 1 receptors. Selective non-nucleotide antagonists have been reported for P2Y 1 , P2Y 2 , P2Y 6 , P2Y 12 , P2Y 13 , P2X 2/3 /P2X 3 and P2X 7 receptors. For example, the dinucleotide INS 37217 (Up 4 dC) potently activates the P2Y 2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X 2/3 /P2X 3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y 1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y 1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC 50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC 50 ) of 0.4 nM at the P2Y 1 receptor, with >10 000-fold selectivity in comparison to P2Y 12 and P2Y 13 receptors. At P2Y 6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. Extracellular purine and pyrimidine nucleotides act as neurotransmitters/modulators . These ubiquitous signalling molecules modulate the function of diverse mammalian cell types and tissues under both normal and pathophysiological conditions. Receptors for extracellular nucleotides have been characterized through medicinal chemical, molecular biological, and pharmacological approaches. The eight subtypes of P2Y receptors, denoted P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 and P2Y 14 , are all seven transmembrane-spanning (7TM) receptors, which couple to G proteins. The seven P2X receptor subunits (P2X 1 -P2X 7 ) form multimeric ligand-gated ion channels. The distribution of P2Y receptors is broad, and the relevant therapeutic interests include antithrombotic therapy, modulation of the immune system and cardiovascular system, and treatment of cystic fibrosis and other pulmonary diseases (Yerxa et al 2002). Several of the

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P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation

Abstract: . P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation.

Cited by 111 publications

References 63 publications

Purinergic receptors and gastrointestinal secretomotor function

Purinergic receptors and gastrointestinal secretomotor function

Inhibition of Apoptosis by P2Y₂Receptor Activation: Novel Pathways for Neuronal Survival

Agonists and Antagonists for P2 Receptors

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P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation

Abstract: . P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation.

Cited by 111 publications

References 63 publications

Purinergic receptors and gastrointestinal secretomotor function

Purinergic receptors and gastrointestinal secretomotor function

Inhibition of Apoptosis by P2Y2Receptor Activation: Novel Pathways for Neuronal Survival

Agonists and Antagonists for P2 Receptors

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Inhibition of Apoptosis by P2Y₂Receptor Activation: Novel Pathways for Neuronal Survival