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  Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca2+ influx through cyclic nucleotide-gated channels.

Bader, A., Bintig, W., Begandt, D., Klett, A., Siller, I. G., Gregor, C., et al. (2017). Adenosine receptors regulate gap junction coupling of the human cerebral microvascular endothelial cells hCMEC/D3 by Ca2+ influx through cyclic nucleotide-gated channels. The Journal of Physiology, 595(8), 2497-2517. doi:10.1113/JP273150.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-E925-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-0906-2
Genre: Journal Article

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2418411.pdf (Publisher version), 2MB
 
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 Creators:
Bader, A., Author
Bintig, W., Author
Begandt, D., Author
Klett, A., Author
Siller, I. G., Author
Gregor, C.1, Author              
Schaarschmidt, F., Author
Weksler, B., Author
Romero, I., Author
Couraud, P. O., Author
Hell, S. W.1, Author              
Ngezahayo, A., Author
Affiliations:
1Department of NanoBiophotonics, MPI for Biophysical Chemistry, Max Planck Society, ou_578627              

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Free keywords: CNG channel; Ca2+ influx; adenosine receptor; blood-brain barrier; cyclic adenosine monophosphate (cAMP); endothelial cell; gap junction
 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.

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Language(s): eng - English
 Dates: 2017-02-142017-04-15
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1113/JP273150
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Title: The Journal of Physiology
Source Genre: Journal
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Pages: - Volume / Issue: 595 (8) Sequence Number: - Start / End Page: 2497 - 2517 Identifier: -