Nau C, Wang G K
Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
J Membr Biol. 2004 Sep 1;201(1):1-8. doi: 10.1007/s00232-004-0702-y.
Voltage-gated Na+ channels are dynamic transmembrane proteins responsible for the rising phase of the action potential in excitable membranes. Local anesthetics (LAs) and structurally related antiarrhythmic and anticonvulsant compounds target specific sites in voltage-gated Na+ channels to block Na+ currents, thus reducing excitability in neuronal, cardiac, or central nervous tissue. A high-affinity LA block is produced by binding to open and inactivated states of Na+ channels rather than to resting states and suggests a binding site that converts from a low- to a high-affinity conformation during gating. Recent findings using site-directed mutagenesis suggest that multiple S6 segments together form an LA binding site within the Na+ channel. While the selectivity filter may form the more extracellular-located part of this binding site, the role of the fast inactivation gate in LA binding has not yet been resolved. The receptor of the neurotoxin batrachotoxin (BTX) is adjacent to or even overlaps with the LA binding site. The close proximity of the LA and BTX binding sites to residues critical for inactivation, together with gating transitions through S6 segments, might explain the strong impact of LAs and BTX on inactivation of voltage-gated Na+ channels and might help elucidate the mechanisms underlying voltage- and frequency-dependent LA block.
电压门控性钠通道是一种动态跨膜蛋白，负责可兴奋膜动作电位的上升期。局部麻醉药（LAs）以及结构相关的抗心律失常和抗惊厥化合物靶向电压门控性钠通道中的特定位点，以阻断钠电流，从而降低神经元、心脏或中枢神经组织的兴奋性。高亲和力的局部麻醉药阻滞是通过与钠通道的开放和失活状态结合而非静息状态结合产生的，这表明存在一个在门控过程中从低亲和力构象转变为高亲和力构象的结合位点。最近使用定点诱变的研究结果表明，多个S6片段共同在钠通道内形成一个局部麻醉药结合位点。虽然选择性过滤器可能构成该结合位点更靠细胞外的部分，但快速失活门在局部麻醉药结合中的作用尚未明确。神经毒素箭毒蛙毒素（BTX）的受体与局部麻醉药结合位点相邻甚至重叠。局部麻醉药和箭毒蛙毒素结合位点与对失活至关重要的残基的紧密接近，以及通过S6片段的门控转变，可能解释了局部麻醉药和箭毒蛙毒素对电压门控性钠通道失活的强烈影响，并可能有助于阐明电压和频率依赖性局部麻醉药阻滞的潜在机制。
