| First Author | Weber EW | Year | 2015 |
| Journal | J Exp Med | Volume | 212 |
| Issue | 11 | Pages | 1883-99 |
| PubMed ID | 26392222 | Mgi Jnum | J:229037 |
| Mgi Id | MGI:5750261 | Doi | 10.1084/jem.20150353 |
| Citation | Weber EW, et al. (2015) TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med 212(11):1883-99 |
| abstractText | Leukocyte transendothelial migration (TEM) is a tightly regulated, multistep process that is critical to the inflammatory response. A transient increase in endothelial cytosolic free calcium ion concentration ( upward arrow[Ca(2+)]i) is required for TEM. However, the mechanism by which endothelial upward arrow[Ca(2+)]i regulates TEM and the channels mediating this upward arrow[Ca(2+)]i are unknown. Buffering upward arrow[Ca(2+)]i in endothelial cells does not affect leukocyte adhesion or locomotion but selectively blocks TEM, suggesting a role for upward arrow[Ca(2+)]i specifically for this step. Transient receptor potential canonical 6 (TRPC6), a Ca(2+) channel expressed in endothelial cells, colocalizes with platelet/endothelial cell adhesion molecule-1 (PECAM) to surround leukocytes during TEM and clusters when endothelial PECAM is engaged. Expression of dominant-negative TRPC6 or shRNA knockdown in endothelial cells arrests neutrophils apically over the junction, similar to when PECAM is blocked. Selectively activating endothelial TRPC6 rescues TEM during an ongoing PECAM blockade, indicating that TRPC6 functions downstream of PECAM. Furthermore, endothelial TRPC6 is required for trafficking of lateral border recycling compartment membrane, which facilitates TEM. Finally, mice lacking TRPC6 in the nonmyeloid compartment (i.e., endothelium) exhibit a profound defect in neutrophil TEM with no effect on leukocyte trafficking. Our findings identify endothelial TRPC6 as the calcium channel mediating the upward arrow[Ca(2+)]i required for TEM at a step downstream of PECAM homophilic interactions. |
