Satin J, Kyle J W, Chen M, Bell P, Cribbs L L, Fozzard H A, Rogart R B
Department of Medicine, University of Chicago, IL 60637.
Science. 1992 May 22;256(5060):1202-5. doi: 10.1126/science.256.5060.1202.
The cardiac sodium channel alpha subunit (RHI) is less sensitive to tetrodotoxin (TTX) and saxitoxin (STX) and more sensitive to cadmium than brain and skeletal muscle (microliter) isoforms. An RHI mutant, with Tyr substituted for Cys at position 374 (as in microliter) confers three properties of TTX-sensitive channels: (i) greater sensitivity to TTX (730-fold); (ii) lower sensitivity to cadmium (28-fold); and (iii) altered additional block by toxin upon repetitive stimulation. Thus, the primary determinant of high-affinity TTX-STX binding is a critical aromatic residue at position 374, and the interaction may take place possibly through an ionized hydrogen bond. This finding requires revision of the sodium channel pore structure that has been previously suggested by homology with the potassium channel.
心脏钠通道α亚基（RHI）对河豚毒素（TTX）和石房蛤毒素（STX）的敏感性低于脑和骨骼肌（微升）亚型，而对镉的敏感性更高。一种RHI突变体，在第374位用酪氨酸取代了半胱氨酸（如同微升亚型），赋予了TTX敏感通道的三个特性：（i）对TTX的敏感性更高（730倍）；（ii）对镉的敏感性更低（28倍）；（iii）重复刺激时毒素的额外阻断发生改变。因此，高亲和力TTX-STX结合的主要决定因素是第374位的关键芳香族残基，并且这种相互作用可能通过离子化氢键发生。这一发现需要对先前通过与钾通道的同源性提出的钠通道孔结构进行修正。
