Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides.
Sulphonylureas stimulate insulin secretion by binding with high-affinity to the sulphonylurea receptor (SUR) subunit of the ATP-sensitive potassium (K(ATP)) channel and thereby closing the channel pore (formed by four Kir6.2 subunits). In the absence of added nucleotides, the maximal block is around...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
2003
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| _version_ | 1797072166649331712 |
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| author | Reimann, F Dabrowski, M Jones, P Gribble, F Ashcroft, F |
| author_facet | Reimann, F Dabrowski, M Jones, P Gribble, F Ashcroft, F |
| author_sort | Reimann, F |
| collection | OXFORD |
| description | Sulphonylureas stimulate insulin secretion by binding with high-affinity to the sulphonylurea receptor (SUR) subunit of the ATP-sensitive potassium (K(ATP)) channel and thereby closing the channel pore (formed by four Kir6.2 subunits). In the absence of added nucleotides, the maximal block is around 60-80 %, indicating that sulphonylureas act as partial antagonists. Intracellular MgADP modulated sulphonylurea block, enhancing inhibition of Kir6.2/SUR1 (beta-cell type) and decreasing that of Kir6.2/SUR2A (cardiac-type) channels. We examined the molecular basis of the different response of channels containing SUR1 and SUR2A, by recording currents from inside-out patches excised from Xenopus oocytes heterologously expressing wild-type or chimeric channels. We used the benzamido derivative meglitinide as this drug blocks Kir6.2/SUR1 and Kir6.2/SUR2A currents, reversibly and with similar potency. Our results indicate that transfer of the region containing transmembrane helices (TMs) 8-11 and the following 65 residues of SUR1 into SUR2A largely confers a SUR1-like response to MgADP and meglitinide, whereas the reverse chimera (SUR128) largely endows SUR1 with a SUR2A-type response. This effect was not specific for meglitinide, as tolbutamide was also unable to prevent MgADP activation of Kir6.2/SUR128 currents. The data favour the idea that meglitinide binding to SUR1 impairs either MgADP binding or the transduction pathway between the NBDs and Kir6.2, and that TMs 8-11 are involved in this modulatory response. The results provide a basis for understanding how beta-cell K(ATP) channels show enhanced sulphonylurea inhibition under physiological conditions, whereas cardiac K(ATP) channels exhibit reduced block in intact cells, especially during metabolic inhibition. |
| first_indexed | 2024-03-06T23:03:46Z |
| format | Journal article |
| id | oxford-uuid:631610cb-639b-41f6-9666-492c3f26201c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:03:46Z |
| publishDate | 2003 |
| record_format | dspace |
| spelling | oxford-uuid:631610cb-639b-41f6-9666-492c3f26201c2022-03-26T18:10:30ZAnalysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:631610cb-639b-41f6-9666-492c3f26201cEnglishSymplectic Elements at Oxford2003Reimann, FDabrowski, MJones, PGribble, FAshcroft, FSulphonylureas stimulate insulin secretion by binding with high-affinity to the sulphonylurea receptor (SUR) subunit of the ATP-sensitive potassium (K(ATP)) channel and thereby closing the channel pore (formed by four Kir6.2 subunits). In the absence of added nucleotides, the maximal block is around 60-80 %, indicating that sulphonylureas act as partial antagonists. Intracellular MgADP modulated sulphonylurea block, enhancing inhibition of Kir6.2/SUR1 (beta-cell type) and decreasing that of Kir6.2/SUR2A (cardiac-type) channels. We examined the molecular basis of the different response of channels containing SUR1 and SUR2A, by recording currents from inside-out patches excised from Xenopus oocytes heterologously expressing wild-type or chimeric channels. We used the benzamido derivative meglitinide as this drug blocks Kir6.2/SUR1 and Kir6.2/SUR2A currents, reversibly and with similar potency. Our results indicate that transfer of the region containing transmembrane helices (TMs) 8-11 and the following 65 residues of SUR1 into SUR2A largely confers a SUR1-like response to MgADP and meglitinide, whereas the reverse chimera (SUR128) largely endows SUR1 with a SUR2A-type response. This effect was not specific for meglitinide, as tolbutamide was also unable to prevent MgADP activation of Kir6.2/SUR128 currents. The data favour the idea that meglitinide binding to SUR1 impairs either MgADP binding or the transduction pathway between the NBDs and Kir6.2, and that TMs 8-11 are involved in this modulatory response. The results provide a basis for understanding how beta-cell K(ATP) channels show enhanced sulphonylurea inhibition under physiological conditions, whereas cardiac K(ATP) channels exhibit reduced block in intact cells, especially during metabolic inhibition. |
| spellingShingle | Reimann, F Dabrowski, M Jones, P Gribble, F Ashcroft, F Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides. |
| title | Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides. |
| title_full | Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides. |
| title_fullStr | Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides. |
| title_full_unstemmed | Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides. |
| title_short | Analysis of the differential modulation of sulphonylurea block of beta-cell and cardiac ATP-sensitive K+ (K(ATP)) channels by Mg-nucleotides. |
| title_sort | analysis of the differential modulation of sulphonylurea block of beta cell and cardiac atp sensitive k k atp channels by mg nucleotides |
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