Polymorphism of cardiac K^+ channel gene and hyperactivity of drugs

获得性长QT综合征多为常用药物阻断心脏Herg K~+通道所致。目前尚不清楚为什么这么多结构多样的化合物会阻断HERG通道，但这种不良的副作用现在被认为是开发新的安全药物的主要障碍。为了确定HERG通道高亲和力药物阻断的结构基础，测定了与Ⅲ类抗心律失常药结合的重要残基：维司力农(强心剂)、E-4031和多非利特(甲磺胺类抗心律失常药)、MS55 1(非甲磺胺类抗心律失常药)和苯丙地尔(多通道阻滞剂)。我们将S6(L646-Y667)的单个残基突变为丙氨酸，并根据与KCSA通道晶体结构的同源性预测了少数几个孔螺旋残基(L622-V625)排列在通道腔和内孔区(Doyle等人，1998年)。Vesnarinone与通道腔内的六个特定残基结合。这一结果发表在《分子药理学》(Kamiya等人，2001)上。此外，急性应用胺碘酮，一种抗心律失常药物，被发现抑制Herg电流，而长期治疗胺碘酮降低了iKs(Kamiya等人。发行量001)。在ALA错义突变位于毛孔螺旋(T623A、S624A和V625A)和S6结构域(G648A、F656A和V659A)的6个通道中，多非利特引起的阻断较少。这六个残基与MK-499上报道的相同。除这些突变体外，MS-551对1655A的阻断作用较小。除F656A外，苯丙地尔不阻断任何S6突变株。这些结果表明：1)甲磺酰胺类药物具有共同和相同的结合部位，2)III类药物与不同的HERG通道残基结合，从而产生不同的药理作用。

Acquired long QT syndrome is most caused by block of cardiac HERG K^+ channels by commonly used medications. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. To determine the structural basis for high-affinity drug block of HERG channels, determined the important residues for drug binding of class III antiarrhythmic agents ; vesnarinone (cardiotonic agent), E-403 1 and dofetilide(a methanesulfonanilide antiarrhythmic drug), MS55 1 (a non-methanesulfonanilide antiarrhythmic drug) and bepridil (multi-channel blocker). We mutated to alanine individual residues of S6 (L646-Y667) and the few residues of the pore helix (L622-V625) predicted to line the channel cavity and inner pore regions based on homology with the solved crystal structure of the KcsA channel (Doyle et al., 1998). Vesnarinone bound to six specific residues within the channel cavity. This result was published in Molecular Pharmacology (Kamiya et al., 2001). In addition, acute application of amiodarone, an antiarrhythmic agent, was found to inhibit HERG current, whereas long-term treatment of amiodarone decreased Iks (Kamiya et al. Circulation 001). Dofetilide caused less block in six channels with Ala missense mutations located in the pore helix (T623A, S624A and V625A) and the S6 domain (G648A, F656A and V659A). These six residues are identical to those reported on MK-499. In addition to these mutants, MS-551 caused less block on 1655A. Bepridil did not block any of S6 mutants except F656A. These results suggest that 1) methanesulfonanilide drugs have common and identical binding sites, 2) class III drugs binds to different residues of HERG channels, hereby producing different pharmacological effects.