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


CONCLUSIONS
Our results show that gliclazide is a sulphonylurea with high affinity and strong selectivity for the beta-cell type of K(ATP) channel.
Gribble
F M
FM
University Laboratory of Physiology, Oxford, UK.
Ashcroft
F M
FM
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D015870:Gene Expression; D005907:Gliclazide / Q000737:chemistry / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000737:chemistry / Q000187:drug effects*; D051379:Mice; D009130:Muscle, Smooth / Q000737:chemistry; D009206:Myocardium / Q000737:chemistry; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology; D014982:Xenopus laevis
D015221:Potassium Channels; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005907:Gliclazide