Prostaglandin E Inhibits Histamine-Evoked Ca Release in Human Aortic Smooth Muscle Cells Through Hyperactive CAMP Signaling Junctions and Protein Kinase A

In human aortic smooth muscle cells, prostaglandin E (PGE) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca concentration evoked by activation of histamine H receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca signals by PGE Exchange proteins activated by cAMP were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE had no effect on the Ca signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP) receptors by photolysis of caged IP The rate of Ca removal from the cytosol was unaffected by PGE, but PGE attenuated histamine-evoked IP accumulation. Substantial inhibition of AC had no effect on the concentration-dependent inhibition of Ca signals by PGE or butaprost (to activate EP receptors selectively), but it modestly attenuated responses to EP receptors, activation of which generated less cAMP than EP receptors. We conclude that inhibition of histamine-evoked Ca signals by PGE occurs through "hyperactive signaling junctions," wherein cAMP is locally delivered to PKA at supersaturating concentrations to cause uncoupling of H receptors from phospholipase C. This sequence allows digital signaling from PGE receptors, through cAMP and PKA, to histamine-evoked Ca signals.