TY  - JOUR
A1  - Pleli, Thomas
A1  - Mondorf, Antonia Maria
A1  - Ferreirós Bouzas, Nerea
A1  - Thomas, Dominique Jeanette
A1  - Dvorak, Karel
A1  - Biondi, Ricardo M.
A1  - Meyer zu Heringdorf, Dagmar
A1  - Zeuzem, Stefan
A1  - Geisslinger, Gerd
A1  - Zimmermann, Herbert
A1  - Waidmann, Oliver
A1  - Piiper, Albrecht
T1  - Activation of adenylyl cyclase causes stimulation of adenosine receptors
T2  - Cellular physiology and biochemistry
N2  - Background/Aims: Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear.
Methods: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA.
Results: Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors). In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors. 
Conclusion: Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.
KW  - adenosine receptors
KW  - cAMP
KW  - Adenylyl cyclase
KW  - eNPP2
KW  - MRP4
KW  - PKA
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46497
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-464977
SN  - 1421-9778
SN  - 1015-8987
N1  - This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.
VL  - 45
IS  - 6
SP  - 2516
EP  - 2528
PB  - Karger
CY  - Basel
ER  -