| Autor: |
Taylor EJA; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom., Pantazaka E; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom., Shelley KL; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom., Taylor CW; Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom cwt1000@cam.ac.uk. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular pharmacology [Mol Pharmacol] 2017 Nov; Vol. 92 (5), pp. 533-545. Date of Electronic Publication: 2017 Sep 06. |
| DOI: |
10.1124/mol.117.109249 |
| Abstrakt: |
In human aortic smooth muscle cells, prostaglandin E 2 (PGE 2 ) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca 2+ concentration evoked by activation of histamine H 1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca 2+ signals by PGE 2 Exchange proteins activated by cAMP were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE 2 had no effect on the Ca 2+ signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP 3 ) receptors by photolysis of caged IP 3 The rate of Ca 2+ removal from the cytosol was unaffected by PGE 2 , but PGE 2 attenuated histamine-evoked IP 3 accumulation. Substantial inhibition of AC had no effect on the concentration-dependent inhibition of Ca 2+ signals by PGE 2 or butaprost (to activate EP 2 receptors selectively), but it modestly attenuated responses to EP 4 receptors, activation of which generated less cAMP than EP 2 receptors. We conclude that inhibition of histamine-evoked Ca 2+ signals by PGE 2 occurs through "hyperactive signaling junctions," wherein cAMP is locally delivered to PKA at supersaturating concentrations to cause uncoupling of H 1 receptors from phospholipase C. This sequence allows digital signaling from PGE 2 receptors, through cAMP and PKA, to histamine-evoked Ca 2+ signals.
(Copyright © 2017 by The Author(s).) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
