Dörschner H, Brekardin E, Uhde I, Schwanstecher C, Schwanstecher M
Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstrabetae 1, 38106 Braunschweig, Germany.
Mol Pharmacol. 1999 Jun;55(6):1060-6. doi: 10.1124/mol.55.6.1060.
Hypoglycemic sulfonylureas (e.g., glibenclamide, glipizide, and tolbutamide) exert their stimulatory effect on excitatory cells by closure of ATP-sensitive potassium (KATP) channels. These channels are heteromultimers composed with a 4:4 stoichiometry of an inwardly rectifying K+ channel (KIR) subunit 6.x plus a sulfonylurea receptor (SUR). SUR1/KIR6.2 reconstitutes the neuronal/pancreatic beta-cell channel, whereas SUR2A/KIR6.2 and SUR2B/KIR6.1 (or KIR6.2) are proposed to reconstitute the cardiac and the vascular smooth muscle-type KATP channels, respectively. SUR2A and SUR2B are splice variants of a single gene differing only in their C-terminal 42 amino acids. Affinities of sulfonylureas for rat SUR2A, rat or human SUR2B, and a SUR2 chimera containing the C-terminal 42 amino acids of SUR1 did not differ significantly, implying that the C terminus does not form part of the binding pocket. Consistent with these findings, reconstituted SUR2A/KIR6.2 and SUR2B/KIR6.2 channels revealed similar sensitivities for glibenclamide and tolbutamide. Dissociation constants of sulfonylureas for SUR2A and SUR2B were 10- to 400-fold higher than for SUR1, however, amazingly the benzoic acid derivative meglitinide did not show lower affinity for SUR2 isoforms. Potencies of glibenclamide, glipizide, tolbutamide, and meglitinide to inhibit activity of SUR1/KIR6.2 and SUR2B/KIR6.2 channels were 3- to 6-fold higher than binding affinities of these drugs with concentration-inhibition relations being significantly steeper (Hill coefficients 1.23-1.32) than binding curves (Hill coefficients 0.93-1.06). The data establish that the C terminus of SURs does not affect sulfonylurea affinity and sensitivity. We conclude that occupation of one of the four SUR sites per channel complex is sufficient to induce KATP channel closure.
降血糖磺脲类药物（如格列本脲、格列吡嗪和甲苯磺丁脲）通过关闭ATP敏感性钾（KATP）通道对兴奋性细胞发挥刺激作用。这些通道是异源多聚体，由内向整流钾（KIR）通道亚基6.x与磺脲类受体（SUR）按4:4化学计量比组成。SUR1/KIR6.2构成神经元/胰腺β细胞通道，而SUR2A/KIR6.2和SUR2B/KIR6.1（或KIR6.2）分别被认为构成心脏和血管平滑肌型KATP通道。SUR2A和SUR2B是单个基因的剪接变体，仅在其C末端42个氨基酸上有所不同。磺脲类药物对大鼠SUR2A、大鼠或人类SUR2B以及含有SUR1 C末端42个氨基酸的SUR2嵌合体的亲和力没有显著差异，这意味着C末端不构成结合口袋的一部分。与这些发现一致，重组的SUR2A/KIR6.2和SUR2B/KIR6.2通道对格列本脲和甲苯磺丁脲表现出相似的敏感性。然而，磺脲类药物对SUR2A和SUR2B的解离常数比对SUR1高10至400倍，令人惊讶的是，苯甲酸衍生物米格列奈对SUR2亚型并未表现出较低的亲和力。格列本脲、格列吡嗪、甲苯磺丁脲和米格列奈抑制SUR1/KIR6.2和SUR2B/KIR6.2通道活性的效力比这些药物的结合亲和力高3至6倍，浓度抑制关系比结合曲线（希尔系数0.93 - 1.06）明显更陡峭（希尔系数1.23 - 1.32）。数据表明SURs的C末端不影响磺脲类药物的亲和力和敏感性。我们得出结论，每个通道复合物的四个SUR位点之一被占据就足以诱导KATP通道关闭。
