Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels.
Long chain fatty acid esters of coenzyme A (LC-CoA) are potent activators of ATP-sensitive (K(ATP)) channels, and elevated levels have been implicated in the pathophysiology of type 2 diabetes. This stimulatory effect is thought to involve a mechanism similar to phosphatidylinositol 4,5-bisphosphate...
| Автори: | , , , , , , , , |
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| Формат: | Journal article |
| Мова: | English |
| Опубліковано: |
2005
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| _version_ | 1826268046652604416 |
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| author | Rapedius, M Soom, M Shumilina, E Schulze, D Schönherr, R Kirsch, C Lang, F Tucker, S Baukrowitz, T |
| author_facet | Rapedius, M Soom, M Shumilina, E Schulze, D Schönherr, R Kirsch, C Lang, F Tucker, S Baukrowitz, T |
| author_sort | Rapedius, M |
| collection | OXFORD |
| description | Long chain fatty acid esters of coenzyme A (LC-CoA) are potent activators of ATP-sensitive (K(ATP)) channels, and elevated levels have been implicated in the pathophysiology of type 2 diabetes. This stimulatory effect is thought to involve a mechanism similar to phosphatidylinositol 4,5-bisphosphate (PIP2), which activates all known inwardly rectifying potassium (Kir) channels. However, the effect of LC-CoA on other Kir channels has not been well characterized. In this study, we show that in contrast to their stimulatory effect on K(ATP) channels, LC-CoA (e.g. oleoyl-CoA) potently and reversibly inhibits all other Kir channels tested (Kir1.1, Kir2.1, Kir3.4, Kir7.1). We also demonstrate that the inhibitory potency of the LC-CoA increases with the chain length of the fatty acid chain, while both its activatory and inhibitory effects critically depend on the presence of the 3'-ribose phosphate on the CoA group. Biochemical studies also demonstrate that PIP2 and LC-CoA bind with similar affinity to the C-terminal domains of Kir2.1 and Kir6.2 and that PIP2 binding can be competitively antagonized by LC-CoA, suggesting that the mechanism of LC-CoA inhibition involves displacement of PIP2. Furthermore, we demonstrate that in contrast to its stimulatory effect on K(ATP) channels, phosphatidylinositol 3,4-bisphosphate has an inhibitory effect on Kir1.1 and Kir2.1. These results demonstrate a bi-directional modulation of Kir channel activity by LC-CoA and phosphoinositides and suggest that changes in fatty acid metabolism (e.g. LC-CoA production) could have profound and widespread effects on cellular electrical activity. |
| first_indexed | 2024-03-06T21:03:36Z |
| format | Journal article |
| id | oxford-uuid:3bb49a30-dbdc-41f4-8a94-6d2067c4483a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:03:36Z |
| publishDate | 2005 |
| record_format | dspace |
| spelling | oxford-uuid:3bb49a30-dbdc-41f4-8a94-6d2067c4483a2022-03-26T14:09:12ZLong chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:3bb49a30-dbdc-41f4-8a94-6d2067c4483aEnglishSymplectic Elements at Oxford2005Rapedius, MSoom, MShumilina, ESchulze, DSchönherr, RKirsch, CLang, FTucker, SBaukrowitz, TLong chain fatty acid esters of coenzyme A (LC-CoA) are potent activators of ATP-sensitive (K(ATP)) channels, and elevated levels have been implicated in the pathophysiology of type 2 diabetes. This stimulatory effect is thought to involve a mechanism similar to phosphatidylinositol 4,5-bisphosphate (PIP2), which activates all known inwardly rectifying potassium (Kir) channels. However, the effect of LC-CoA on other Kir channels has not been well characterized. In this study, we show that in contrast to their stimulatory effect on K(ATP) channels, LC-CoA (e.g. oleoyl-CoA) potently and reversibly inhibits all other Kir channels tested (Kir1.1, Kir2.1, Kir3.4, Kir7.1). We also demonstrate that the inhibitory potency of the LC-CoA increases with the chain length of the fatty acid chain, while both its activatory and inhibitory effects critically depend on the presence of the 3'-ribose phosphate on the CoA group. Biochemical studies also demonstrate that PIP2 and LC-CoA bind with similar affinity to the C-terminal domains of Kir2.1 and Kir6.2 and that PIP2 binding can be competitively antagonized by LC-CoA, suggesting that the mechanism of LC-CoA inhibition involves displacement of PIP2. Furthermore, we demonstrate that in contrast to its stimulatory effect on K(ATP) channels, phosphatidylinositol 3,4-bisphosphate has an inhibitory effect on Kir1.1 and Kir2.1. These results demonstrate a bi-directional modulation of Kir channel activity by LC-CoA and phosphoinositides and suggest that changes in fatty acid metabolism (e.g. LC-CoA production) could have profound and widespread effects on cellular electrical activity. |
| spellingShingle | Rapedius, M Soom, M Shumilina, E Schulze, D Schönherr, R Kirsch, C Lang, F Tucker, S Baukrowitz, T Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. |
| title | Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. |
| title_full | Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. |
| title_fullStr | Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. |
| title_full_unstemmed | Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. |
| title_short | Long chain CoA esters as competitive antagonists of phosphatidylinositol 4,5-bisphosphate activation in Kir channels. |
| title_sort | long chain coa esters as competitive antagonists of phosphatidylinositol 4 5 bisphosphate activation in kir channels |
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