Calcium-inhibited adenylyl cyclase (AC6) controls endothelial cell barrier function

Abstract

For many years, investigators have recognized that inflammatory mediators increase cytosolic calcium in endothelial cells, which triggers intercellular gap formation and increased permeability. However, this calcium-mediated increase in permeability occurs only when cAMP levels are not also increased. Indeed, a rise in cAMP prevents inflammatory mediators from increasing permeability, and it even reverses tissue edema that has already been initiated. Studies examining the crosstalk between cytosolic calcium and cAMP reveal an inverse relationship, where increased cytosolic calcium decreases cAMP. Endothelial cell expression of a type 6 (calcium-inhibited) adenylyl cyclase is responsible for this action, so that calcium entry across the cell membrane decreases cAMP synthesis. Eliminating calcium inhibition of cAMP prevents inflammatory mediators from increasing endothelial cell permeability, indicating that crosstalk between these intracellular messengers is necessary for the endothelium to change its shape. © 2005 Humana Press Inc.