Acute internalization of gap junctions in vascular endothelial cells in response to inflammatory mediator-induced G-protein coupled receptor activation.
During the inflammatory response, activation of G-protein coupled receptors (GPCRs) by inflammatory mediators rapidly leads to inhibition of gap junction intercellular communication (GJIC); however, the steps that lead to this inhibition are not known. Combining high-resolution fluorescence microscopy and functional assays, we found that activation of the GPCRs PAR-1 and ET(A/B) by their natural inflammatory mediator agonists, thrombin and endothelin-1, resulted in rapid and acute internalization of gap junctions (GJs) that coincided with the inhibition of GJIC followed by increased vascular permeability. The endocytosis protein clathrin and the scaffold protein ZO-1 appeared to be involved in GJ internalization, and ZO-1 was partially displaced from GJs during the internalization process. These findings demonstrate that GJ internalization is an efficient mechanism for modulating GJIC in inflammatory response.
Baker
Susan M
SM
Department of Biological Sciences, Lehigh University, 111 Research Drive, Iacocca Hall, Bethlehem, PA 18015, USA.
Kim
Namho
N
Gumpert
Anna M
AM
Segretain
Dominique
D
Falk
Matthias M
MM
D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D010539:Permeability; D010750:Phosphoproteins / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000819:agonists / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology; D062826:Zonula Occludens-1 Protein
D002966:Clathrin; D019332:Endothelin-1; D008565:Membrane Proteins; D010750:Phosphoproteins; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D044463:Receptor, PAR-1; D043562:Receptors, G-Protein-Coupled; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D013917:Thrombin