The critical role of intracellular zinc in adenosine A2 receptor activation induced cardioprotection against reperfusion injury

Neural cell adhesion molecule (NCAM) associates with fibroblast growth factor (FGF) receptor-1 (FGFR1). However, the biological significance of this interaction remains largely elusive. In this study, we show that NCAM induces a specific, FGFR1-mediated cellular response that is remarkably different from that elicited by FGF-2. In contrast to FGF-induced degradation of endocytic FGFR1, NCAM promotes the stabilization of the receptor, which is recycled to the cell surface in a Rab11- and Src-dependent manner. In turn, FGFR1 recycling is required for NCAM-induced sustained activation of various effectors. Furthermore, NCAM, but not FGF-2, promotes cell migration, and this response depends on FGFR1 recycling and sustained Src activation. Our results implicate NCAM as a nonconventional ligand for FGFR1 that exerts a peculiar control on the intracellular trafficking of the receptor, resulting in a specific cellular response. Besides introducing a further level of complexity in the regulation of FGFR1 function, our findings highlight the link of FGFR recycling with sustained signaling and cell migration and the critical role of these events in dictating the cellular response evoked by receptor activation.

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Critical role of reactive nitrogen species in lung ischemia–reperfusion injury

The Journal of Heart and Lung Transplantation ◽

10.1016/s1053-2498(02)00556-9 ◽

2003 ◽

Vol 22 (7) ◽

pp. 784-793 ◽

Cited By ~ 42

Author(s):

Babu V Naidu ◽

Charles Fraga ◽

Andrew L Salzman ◽

Csaba Szabo ◽

Edward D Verrier ◽

...

Keyword(s):

Reperfusion Injury ◽

Reactive Nitrogen Species ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Reactive Nitrogen ◽

Nitrogen Species

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The Critical Role of Transmembrane Prolines in Human Prostacyclin Receptor Activation

Molecular Pharmacology ◽

10.1124/mol.61.5.1202 ◽

2002 ◽

Vol 61 (5) ◽

pp. 1202-1210 ◽

Cited By ~ 30

Author(s):

Jeremiah Stitham ◽

Kathleen A. Martin ◽

John Hwa

Keyword(s):

Critical Role ◽

Receptor Activation ◽

Prostacyclin Receptor

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The critical role of reactive nitrogen species in lung ischemia reperfusion injury

The Journal of Heart and Lung Transplantation ◽

10.1016/s1053-2498(01)00657-x ◽

2002 ◽

Vol 21 (1) ◽

pp. 135 ◽

Cited By ~ 3

Author(s):

B.V Naidu ◽

B Krishnadasan ◽

C Fraga ◽

R Thomas ◽

A.L Salzman ◽

...

Keyword(s):

Reperfusion Injury ◽

Reactive Nitrogen Species ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Reactive Nitrogen ◽

Nitrogen Species

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The Ig-like domain of human GM-CSF receptor α plays a critical role in cytokine binding and receptor activation

Biochemical Journal ◽

10.1042/bj20091745 ◽

2010 ◽

Vol 426 (3) ◽

pp. 307-317 ◽

Cited By ~ 16

Author(s):

Shamaruh Mirza ◽

Andrew Walker ◽

Jinglong Chen ◽

James M. Murphy ◽

Ian G. Young

Keyword(s):

Structural Alignment ◽

Critical Role ◽

Receptor Activation ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Subsequent Activation ◽

Macrophage Colony ◽

Key Residues ◽

Stimulating Factor

GM-CSF (granulocyte/macrophage colony-stimulating factor) is an important mediator of inducible haemopoiesis and inflammation, and has a critical role in the function of alveolar macrophages. Its clinical applications include the mobilization of haemopoietic progenitors, and a role as an immune stimulant and vaccine adjuvant in cancer patients. GM-CSF signals via a specific α receptor (GM-CSFRα) and the shared hβc (human common β-subunit). The present study has investigated the role of the Ig-like domain of GM-CSFRα in GM-CSF binding and signalling. Deletion of the Ig-like domain abolished direct GM-CSF binding and decreased growth signalling in the presence of hβc. To locate the specific residues in the Ig-like domain of GM-CSFRα involved in GM-CSF binding, a structural alignment was made with a related receptor, IL-13Rα1 (interleukin-13 receptor α1), whose structure and mode of interaction with its ligand has recently been elucidated. Mutagenesis of candidate residues in the predicted region of interaction identified Val51 and Cys60 as having critical roles in binding to the α receptor, with Arg54 and Leu55 also being important. High-affinity binding in the presence of hβc was strongly affected by mutation of Cys60 and was also reduced by mutation of Val51, Arg54 and Leu55. Of the four key residues, growth signalling was most severely affected by mutation of Cys60. The results indicate a previously unrecognized role for the Ig-like domain, and in particular Cys60, of GM-CSFRα in the binding of GM-CSF and subsequent activation of cellular signalling.

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Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury

Hepatology ◽

10.1002/hep.21285 ◽

2006 ◽

Vol 44 (3) ◽

pp. 561-572 ◽

Cited By ~ 79

Author(s):

Laura Llacuna ◽

Montserrat Marí ◽

Carmen Garcia-Ruiz ◽

José C. Fernandez-Checa ◽

Albert Morales

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

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Abstract 15175: Critical Role of Sodium-Glucose Cotransporter 1 in the Cardioprotection Through the Maintenance of Energy Production During Ischemia-Reperfusion Injury

Circulation ◽

10.1161/circ.130.suppl_2.15175 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yusuke Kashiwagi ◽

Tomohisa Nagoshi ◽

Takuya Yoshino ◽

Ryuko Anzawa ◽

Michihiro Yoshimura

Keyword(s):

Reperfusion Injury ◽

Energy Production ◽

Glucose Utilization ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Glucose Transporters ◽

Sodium Glucose Cotransporter ◽

Atp Generation

Glucose becomes an important preferential substrate for cardiac metabolism and ATP generation under specific pathological conditions, such as ischemia. Glucose utilization is initiated by glucose uptake, which is mainly controlled by glucose transporters. Although the role of passive glucose transporters (GLUTs) has been investigated intensively, little is known about the functional significance of the other active transporter, sodium-glucose cotransporter 1 (SGLT1), in the heart. We herein hypothesized that cardiac SGLT1 plays a critical role for cardioprotection during ischemia-reperfusion injury (IRI), possibly through the enhanced glucose utilization for the energy production. To test this, we studied the effects of 10-4 M of phlorizin, SGLT1 inhibitor, on the baseline function and its response to global ischemia (20 minutes)-reperfusion (40 minutes) injury in mouse Langendorff perfusion model, where SGLT1, but not SGLT2, is highly expressed, as confirmed by immunoblotting assay. Although phlorizin did not affect baseline function, its administration during IRI significantly impaired recovery in left ventricular contraction (% recovery of baseline; 67.3±4.5 vs. 89.7±6.8%, n=5 each, P<0.05) and rate pressure product (18600±1290 vs. 25100±1010 mmHg•bpm, n=5 each, P<0.01), associated with increased infarct size demonstrated by TTC staining as well as CPK activity released into the perfusate (20.8±9.5 vs. 2.0±0.6 U•g, n≥3, P<0.05). Of note, the onset of ischemic contracture, which is thought to be initiated by ATP depletion in cardiomyocytes, was earlier with phlorizin perfusion (288±21 vs. 364±27 sec, n≥8, P<0.05). Consistent with this, the significant reduction of tissue ATP content was observed in phlorizin perfused heart (4.81±0.61 vs. 6.87±0.13 μmol/g tissue, n≥4, P<0.05). In conclusion, these data demonstrate that SGLT1 represents an important cardioprotective mechanism against IRI possibly through the maintenance of ATP generation. Our findings shed new light on the essential role of SGLT1 for the optimization of cardiac energy metabolism by the enhanced glucose availability during ischemia, thus leading to substantial myocardial protection after severe ischemic insults.

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