Differential sensitivity of beta-cell and extrapancreatic K(ATP) channels to gliclazide.

Journal article

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.

Authors: Gribble, F; Ashcroft, F

• Publication status: Published
• Journal: Diabetologia
• Volume: 42
• Issue: 7
• Pages: 845-848
• Publication date: 1999-07-01
• DOI: 10.1007/s001250051236
• EISSN: 1432-0428
• ISSN: 0012-186X
• Language: English
• Keywords: Potassium Channels; Tolbutamide; Adenosine Triphosphate; Xenopus laevis; Muscle, Smooth; Rats; Islets of Langerhans; Sulfonylurea Compounds; Animals; Cells, Cultured; Myocardium; Gene Expression; Mice; Binding Sites; Gliclazide; Patch-Clamp Techniques