The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide.
The ATP-sensitive K-channel (K-ATP channel) plays a key role in insulin secretion from pancreatic beta-cells. It is closed by glucose metabolism, which stimulates insulin secretion, and opened by the drug diazoxide, which inhibits insulin release. Metabolic regulation is mediated by changes in ATP a...
| Main Authors: | , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
1997
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| _version_ | 1797076936042741760 |
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| author | Gribble, F Tucker, S Ashcroft, F |
| author_facet | Gribble, F Tucker, S Ashcroft, F |
| author_sort | Gribble, F |
| collection | OXFORD |
| description | The ATP-sensitive K-channel (K-ATP channel) plays a key role in insulin secretion from pancreatic beta-cells. It is closed by glucose metabolism, which stimulates insulin secretion, and opened by the drug diazoxide, which inhibits insulin release. Metabolic regulation is mediated by changes in ATP and Mg-ADP, which inhibit and potentiate channel activity, respectively. The beta-cell K-ATP channel consists of a pore-forming subunit, Kir6.2, and a regulatory subunit, SUR1. We have mutated (independently or together) two lysine residues in the Walker A (W(A)) motifs of the first (K719A) and second (K1384M) nucleotide-binding domains (NBDs) of SUR1. These mutations are expected to inhibit nucleotide hydrolysis. Our results indicate that the W(A) lysine of NBD1 (but not NBD2) is essential for activation of K-ATP currents by diazoxide. The potentiatory effects of Mg-ADP required the presence of the W(A) lysines in both NBDs. Mutant currents were slightly more sensitive to ATP than wild-type currents. Metabolic inhibition led to activation of wild-type and K1384M currents, but not K719A or K719A/K1384M currents, suggesting that there may be a factor in addition to ATP and ADP which regulates K-ATP channel activity. |
| first_indexed | 2024-03-07T00:10:41Z |
| format | Journal article |
| id | oxford-uuid:79212f69-74ba-43ff-962b-2bf5eb05483b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:10:41Z |
| publishDate | 1997 |
| record_format | dspace |
| spelling | oxford-uuid:79212f69-74ba-43ff-962b-2bf5eb05483b2022-03-26T20:35:18ZThe essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:79212f69-74ba-43ff-962b-2bf5eb05483bEnglishSymplectic Elements at Oxford1997Gribble, FTucker, SAshcroft, FThe ATP-sensitive K-channel (K-ATP channel) plays a key role in insulin secretion from pancreatic beta-cells. It is closed by glucose metabolism, which stimulates insulin secretion, and opened by the drug diazoxide, which inhibits insulin release. Metabolic regulation is mediated by changes in ATP and Mg-ADP, which inhibit and potentiate channel activity, respectively. The beta-cell K-ATP channel consists of a pore-forming subunit, Kir6.2, and a regulatory subunit, SUR1. We have mutated (independently or together) two lysine residues in the Walker A (W(A)) motifs of the first (K719A) and second (K1384M) nucleotide-binding domains (NBDs) of SUR1. These mutations are expected to inhibit nucleotide hydrolysis. Our results indicate that the W(A) lysine of NBD1 (but not NBD2) is essential for activation of K-ATP currents by diazoxide. The potentiatory effects of Mg-ADP required the presence of the W(A) lysines in both NBDs. Mutant currents were slightly more sensitive to ATP than wild-type currents. Metabolic inhibition led to activation of wild-type and K1384M currents, but not K719A or K719A/K1384M currents, suggesting that there may be a factor in addition to ATP and ADP which regulates K-ATP channel activity. |
| spellingShingle | Gribble, F Tucker, S Ashcroft, F The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. |
| title | The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. |
| title_full | The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. |
| title_fullStr | The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. |
| title_full_unstemmed | The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. |
| title_short | The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. |
| title_sort | essential role of the walker a motifs of sur1 in k atp channel activation by mg adp and diazoxide |
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