Prostaglandin E2 Inhibits Histamine-Evoked Ca2+ Release in Human Aortic Smooth Muscle Cells through Hyperactive cAMP Signaling Junctions and Protein Kinase A.

Emily J A Taylor,Kathryn L Shelley,Colin W Taylor,Evangelia Pantazaka

doi:10.1124/mol.117.109249

Emily J A Taylor, Kathryn L Shelley + Show 2 more

Open Access

https://doi.org/10.1124/mol.117.109249

Copy DOI

Journal: Molecular pharmacology	Publication Date: Sep 6, 2017
Citations: 10	License type: cc-by

Affiliation: University of Cambridge

Abstract

In human aortic smooth muscle cells, prostaglandin E2 (PGE2) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca2+ concentration evoked by activation of histamine H1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca2+ signals by PGE2. Exchange proteins activated by cAMP were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE2 had no effect on the Ca2+ signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP3) receptors by photolysis of caged IP3. The rate of Ca2+ removal from the cytosol was unaffected by PGE2, but PGE2 attenuated histamine-evoked IP3 accumulation. Substantial inhibition of AC had no effect on the concentration-dependent inhibition of Ca2+ signals by PGE2 or butaprost (to activate EP2 receptors selectively), but it modestly attenuated responses to EP4 receptors, activation of which generated less cAMP than EP2 receptors. We conclude that inhibition of histamine-evoked Ca2+ signals by PGE2 occurs through “hyperactive signaling junctions,” wherein cAMP is locally delivered to PKA at supersaturating concentrations to cause uncoupling of H1 receptors from phospholipase C. This sequence allows digital signaling from PGE2 receptors, through cAMP and PKA, to histamine-evoked Ca2+ signals.

Highlights

Ca21 and cAMP are ubiquitous intracellular messengers that regulate most cellular behaviors
We conclude that inhibition of histamine-evoked Ca21 signals by prostaglandin E2 (PGE2) is not mediated by inhibition of cyclic nucleotide phosphodiesterase (PDE) and consequent accumulation of cGMP
We considered whether A kinase-anchoring protein (AKAP), which are widely implicated in assembling protein kinase (PKA) with its regulators and effectors (Smith et al, 2017), might contribute to organization of the cAMP signaling through PKA that leads to inhibition of histamine-evoked Ca21 signals

Summary

Introduction

Ca21 and cAMP are ubiquitous intracellular messengers that regulate most cellular behaviors The versatility of these messengers depends on both the spatiotemporal organization of the changes in their concentration within cells (Cooper and Tabbasum, 2014) and on interactions between them [see references in Tovey et al (2008)]. These interactions are important in many smooth muscles, where increases in intracellular free Ca21 concentration ([Ca21]i) stimulate contraction, but receptors that stimulate formation of cAMP usually cause relaxation. At least some of these effects may be through exchange proteins activated by cAMP (EPACs), probably EPAC 1, which is abundant in blood vessels within endothelial cells (Roscioni et al, 2011)

Methods

Results

Conclusion