A Gs-coupled purinergic receptor boosts Ca2+ influx and vascular contractility during diabetic hyperglycemia
| Title: | A Gs-coupled purinergic receptor boosts Ca2+ influx and vascular contractility during diabetic hyperglycemia |
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| Authors: | Maria Paz Prada, Arsalan U Syed, Olivia R Buonarati, Gopireddy R Reddy, Matthew A Nystoriak, Debapriya Ghosh, Sergi Simó, Daisuke Sato, Kent C Sasse, Sean M Ward, Luis F Santana, Yang K Xiang, Johannes W Hell, Madeline Nieves-Cintrón, Manuel F Navedo |
| Source: | eLife, Vol 8 (2019) |
| Publisher Information: | eLife Sciences Publications Ltd, 2019. |
| Publication Year: | 2019 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | extracellular nucleotides, arterial tone, ion channels, biosensors, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | Elevated glucose increases vascular reactivity by promoting L-type CaV1.2 channel (LTCC) activity by protein kinase A (PKA). Yet, how glucose activates PKA is unknown. We hypothesized that a Gs-coupled P2Y receptor is an upstream activator of PKA mediating LTCC potentiation during diabetic hyperglycemia. Experiments in apyrase-treated cells suggested involvement of a P2Y receptor underlying the glucose effects on LTTCs. Using human tissue, expression for P2Y11, the only Gs-coupled P2Y receptor, was detected in nanometer proximity to CaV1.2 and PKA. FRET-based experiments revealed that the selective P2Y11 agonist NF546 and elevated glucose stimulate cAMP production resulting in enhanced PKA-dependent LTCC activity. These changes were blocked by the selective P2Y11 inhibitor NF340. Comparable results were observed in mouse tissue, suggesting that a P2Y11-like receptor is mediating the glucose response in these cells. These findings established a key role for P2Y11 in regulating PKA-dependent LTCC function and vascular reactivity during diabetic hyperglycemia. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/42214; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.42214 |
| Access URL: | https://doaj.org/article/834ddbe5b2af4b2d9cbfe39b3182cbe7 |
| Accession Number: | edsdoj.834ddbe5b2af4b2d9cbfe39b3182cbe7 |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
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| DOI: | 10.7554/eLife.42214 |
| Published in: | eLife |
| Language: | English |