Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide.
AIMS/HYPOTHESIS: To investigate the tissue specificity of gliclazide for cloned beta-cell, cardiac and smooth muscle ATP-sensitive K-channels (K(ATP) channels). These channels share a common pore-forming subunit, Kir6.2, which associates with different sulphonylurea receptor isoforms (SUR1 in beta-c...
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| Format: | Journal article |
| Language: | English |
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1999
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| _version_ | 1826305766857900032 |
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| author | Gribble, F Ashcroft, F |
| author_facet | Gribble, F Ashcroft, F |
| author_sort | Gribble, F |
| collection | OXFORD |
| description | AIMS/HYPOTHESIS: To investigate the tissue specificity of gliclazide for cloned beta-cell, cardiac and smooth muscle ATP-sensitive K-channels (K(ATP) channels). These channels share a common pore-forming subunit, Kir6.2, which associates with different sulphonylurea receptor isoforms (SUR1 in beta-cells, SUR2A in heart, SUR2B in smooth muscle). METHODS: Kir6.2 was coexpressed with SUR1, SUR2A or SUR2B in Xenopus oocytes, and channel activity was measured by recording macroscopic currents in giant inside-out membrane patches. Gliclazide was added to the intracellular membrane surface. RESULTS: We reported previously that Kir6.2-SUR1 currents are blocked at two sites by tolbutamide: a high-affinity site on SUR1 and a low-affinity site on Kir6.2. We now show that gliclazide also inhibits beta-cell K(ATP) channels at two sites: a high-affinity site, which is half-maximally blocked (Ki) at 50 +/- 7 nmol/l (n = 8) and a low-affinity site with a Ki of 3.0 +/- 0.6 mmol/l (n = 4). The high-affinity site on SUR1 was thus about 40-fold more sensitive to gliclazide than to tolbutamide (Ki approximately 2 micromol/l). Cloned cardiac and smooth muscle K(ATP) channels did not show high-affinity block by gliclazide. Kir6.2-SUR2A currents exhibited a single low-affinity site with a Ki of 0.8 +/- 0.1 mmol/l (n = 5), which is likely to reside on the Kir6.2 subunit. CONCLUSION/INTERPRETATION: Our results show that gliclazide is a sulphonylurea with high affinity and strong selectivity for the beta-cell type of K(ATP) channel. |
| first_indexed | 2024-03-07T06:37:50Z |
| format | Journal article |
| id | oxford-uuid:f844051a-008a-4b3e-9c23-e26211f4b9cc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:37:50Z |
| publishDate | 1999 |
| record_format | dspace |
| spelling | oxford-uuid:f844051a-008a-4b3e-9c23-e26211f4b9cc2022-03-27T12:48:55ZDifferential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f844051a-008a-4b3e-9c23-e26211f4b9ccEnglishSymplectic Elements at Oxford1999Gribble, FAshcroft, FAIMS/HYPOTHESIS: To investigate the tissue specificity of gliclazide for cloned beta-cell, cardiac and smooth muscle ATP-sensitive K-channels (K(ATP) channels). These channels share a common pore-forming subunit, Kir6.2, which associates with different sulphonylurea receptor isoforms (SUR1 in beta-cells, SUR2A in heart, SUR2B in smooth muscle). METHODS: Kir6.2 was coexpressed with SUR1, SUR2A or SUR2B in Xenopus oocytes, and channel activity was measured by recording macroscopic currents in giant inside-out membrane patches. Gliclazide was added to the intracellular membrane surface. RESULTS: We reported previously that Kir6.2-SUR1 currents are blocked at two sites by tolbutamide: a high-affinity site on SUR1 and a low-affinity site on Kir6.2. We now show that gliclazide also inhibits beta-cell K(ATP) channels at two sites: a high-affinity site, which is half-maximally blocked (Ki) at 50 +/- 7 nmol/l (n = 8) and a low-affinity site with a Ki of 3.0 +/- 0.6 mmol/l (n = 4). The high-affinity site on SUR1 was thus about 40-fold more sensitive to gliclazide than to tolbutamide (Ki approximately 2 micromol/l). Cloned cardiac and smooth muscle K(ATP) channels did not show high-affinity block by gliclazide. Kir6.2-SUR2A currents exhibited a single low-affinity site with a Ki of 0.8 +/- 0.1 mmol/l (n = 5), which is likely to reside on the Kir6.2 subunit. CONCLUSION/INTERPRETATION: Our results show that gliclazide is a sulphonylurea with high affinity and strong selectivity for the beta-cell type of K(ATP) channel. |
| spellingShingle | Gribble, F Ashcroft, F Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. |
| title | Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. |
| title_full | Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. |
| title_fullStr | Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. |
| title_full_unstemmed | Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. |
| title_short | Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide. |
| title_sort | differential sensitivity of beta cell and extrapancreatic k atp channels to gliclazide |
| work_keys_str_mv | AT gribblef differentialsensitivityofbetacellandextrapancreatickatpchannelstogliclazide AT ashcroftf differentialsensitivityofbetacellandextrapancreatickatpchannelstogliclazide |