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Regulation of M2‐type pyruvate kinase mediated by the high‐affinity IgE receptors is required for mast cell degranulation
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| Zeitschriftentitel: | British Journal of Pharmacology |
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| Personen und Körperschaften: | , , , , , , , |
| In: | British Journal of Pharmacology, 154, 2008, 5, S. 1035-1046 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| Zusammenfassung: | <jats:sec><jats:title>Background and purpose:</jats:title><jats:p>M<jats:sub>2</jats:sub>‐type pyruvate kinase (M<jats:sub>2</jats:sub>PK) was found to interact directly with the ‘ITAM’ region of the γ chain of the high‐affinity IgE receptor (FcɛRI). Our hypothesis was that mast cell degranulation might require the FcɛRI‐mediated inhibition of M<jats:sub>2</jats:sub>PK activity.</jats:p></jats:sec><jats:sec><jats:title>Experimental approach:</jats:title><jats:p>In rat basophilic leukaemia (RBL‐2H3) cells, the effects of directly inhibiting M<jats:sub>2</jats:sub>PK or preventing the FcɛRI‐mediated inhibition of M<jats:sub>2</jats:sub>PK (disinhibition) on degranulation was measured by hexosaminidase release. Effects of blocking the FcɛRI‐mediated inhibition of M<jats:sub>2</jats:sub>PK was also assessed <jats:italic>in vivo</jats:italic> in a mouse model of allergen‐induced airway hyper‐responsiveness.</jats:p></jats:sec><jats:sec><jats:title>Key results:</jats:title><jats:p>Activation of FcɛRI in RBL‐2H3 cells caused the rapid phosphorylation of tyrosine residues in M<jats:sub>2</jats:sub>PK, associated with a decrease in M<jats:sub>2</jats:sub>PK enzymatic activity. There was an inverse correlation between M<jats:sub>2</jats:sub>PK activity and mast cell degranulation. FcɛRI‐mediated inhibition of M<jats:sub>2</jats:sub>PK involved Src kinase, phosphatidylinositol 3‐kinase, PKC and calcium. Direct inhibition of M<jats:sub>2</jats:sub>PK potentiated FcɛRI‐mediated degranulation and prevention of the FcɛRI‐mediated inhibition of M<jats:sub>2</jats:sub>PK attenuated mast cell degranulation. Transfection of RBL‐2H3 cells with M<jats:sub>1</jats:sub>PK which prevents FcɛRI‐induced inhibition of M<jats:sub>2</jats:sub>PK, markedly reduced their degranulation and exogenous M<jats:sub>1</jats:sub>PK (i.p.) inhibited ovalbumin‐induced airway hyper‐responsiveness <jats:italic>in vivo</jats:italic>.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and implications:</jats:title><jats:p>We have identified a new control point and a novel biochemical pathway in the process of mast cell degranulation. Our study suggests that the FcɛRI‐mediated inhibition of M<jats:sub>2</jats:sub>PK is a crucial step in responses to allergens. Moreover, the manipulation of glycolytic processes and intermediates could provide novel strategies for the treatment of allergic diseases.</jats:p><jats:p><jats:italic>British Journal of Pharmacology</jats:italic> (2008) <jats:bold>154</jats:bold>, 1035–1046; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/bjp.2008.148">10.1038/bjp.2008.148</jats:ext-link>; published online 21 April 2008</jats:p></jats:sec> |
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| Umfang: | 1035-1046 |
| ISSN: |
0007-1188
1476-5381 |
| DOI: | 10.1038/bjp.2008.148 |