Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca2+ influx through cyclic nucleotide-gated channels
Key points Gap junction channels are essential for the formation and regulation of physiological units in tissues by allowing the lateral cell-to-cell diffusion of ions, metabolites and second messengers. Stimulation of the adenosine receptor subtype A2B increases the gap junction coupling in the hu...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
15 April 2017
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| In: |
The journal of physiology
Year: 2017, Volume: 595, Issue: 8, Pages: 2497-2517 |
| ISSN: | 1469-7793 |
| DOI: | 10.1113/JP273150 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1113/JP273150 Verlag, Volltext: https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP273150 
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| Author Notes: | Almke Bader, Willem Bintig, Daniela Begandt, Anne Klett, Ina G. Siller, Carola Gregor, Frank Schaarschmidt, Babette Weksler, Ignacio Romero, Pierre-Olivier Couraud, Stefan W. Hell and Anaclet Ngezahayo |
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| 245 | 1 | 0 | |a Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca2+ influx through cyclic nucleotide-gated channels |c Almke Bader, Willem Bintig, Daniela Begandt, Anne Klett, Ina G. Siller, Carola Gregor, Frank Schaarschmidt, Babette Weksler, Ignacio Romero, Pierre-Olivier Couraud, Stefan W. Hell and Anaclet Ngezahayo |
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| 520 | |a Key points Gap junction channels are essential for the formation and regulation of physiological units in tissues by allowing the lateral cell-to-cell diffusion of ions, metabolites and second messengers. Stimulation of the adenosine receptor subtype A2B increases the gap junction coupling in the human blood-brain barrier endothelial cell line hCMEC/D3. Although the increased gap junction coupling is cAMP-dependent, neither the protein kinase A nor the exchange protein directly activated by cAMP were involved in this increase. We found that cAMP activates cyclic nucleotide-gated (CNG) channels and thereby induces a Ca2+ influx, which leads to the increase in gap junction coupling. The report identifies CNG channels as a possible physiological link between adenosine receptors and the regulation of gap junction channels in endothelial cells of the blood-brain barrier. Abstract The human cerebral microvascular endothelial cell line hCMEC/D3 was used to characterize the physiological link between adenosine receptors and the gap junction coupling in endothelial cells of the blood-brain barrier. Expressed adenosine receptor subtypes and connexin (Cx) isoforms were identified by RT-PCR. Scrape loading/dye transfer was used to evaluate the impact of the A2A and A2B adenosine receptor subtype agonist 2-phenylaminoadenosine (2-PAA) on the gap junction coupling. We found that 2-PAA stimulated cAMP synthesis and enhanced gap junction coupling in a concentration-dependent manner. This enhancement was accompanied by an increase in gap junction plaques formed by Cx43. Inhibition of protein kinase A did not affect the 2-PAA-related enhancement of gap junction coupling. In contrast, the cyclic nucleotide-gated (CNG) channel inhibitor l-cis-diltiazem, as well as the chelation of intracellular Ca2+ with BAPTA, or the absence of external Ca2+, suppressed the 2-PAA-related enhancement of gap junction coupling. Moreover, we observed a 2-PAA-dependent activation of CNG channels by a combination of electrophysiology and pharmacology. In conclusion, the stimulation of adenosine receptors in hCMEC/D3 cells induces a Ca2+ influx by opening CNG channels in a cAMP-dependent manner. Ca2+ in turn induces the formation of new gap junction plaques and a consecutive sustained enhancement of gap junction coupling. The report identifies CNG channels as a physiological link that integrates gap junction coupling into the adenosine receptor-dependent signalling of endothelial cells of the blood-brain barrier. | ||
| 650 | 4 | |a adenosine receptor | |
| 650 | 4 | |a blood-brain barrier | |
| 650 | 4 | |a Ca2+ influx | |
| 650 | 4 | |a CNG channel | |
| 650 | 4 | |a cyclic adenosine monophosphate (cAMP) | |
| 650 | 4 | |a endothelial cell | |
| 650 | 4 | |a gap junction | |
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