Mutant sodium channels, myotonia, and propofol
Mutant sodium channels, myotonia, and propofol
复制标题
钠通道突变、肌强直和异丙酚
DOI：
10.1002/mus.1062
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发表时间：
2001
期刊：
影响因子：
3.4
通讯作者：
J. England
中科院分区：
文献类型：
--
作者：
J. England
先天性副肌强直是一种常染色体显性遗传性肌肉疾病，其特征是冷诱导和运动诱导的肌强直。先天性副肌强直是一组肌肉疾病之一，其是由于编码骨骼肌钠通道a亚基（SCN 4A）的基因中的错义突变引起的。所有这些所谓的肌肉“钠通道病”都有一个肌膜兴奋性异常，可以直接表现为肌强直或肌无力。这些等位基因疾病中有三种表现出典型的肌强直，并被命名为“钠通道肌强直”。目前，已知的钠通道肌强直是先天性副肌强直、高钾性周期性麻痹和钾加重型肌强直。为了避免误解，值得指出的是，无论是强直性肌营养不良还是先天性肌强直都不是由于肌肉钠离子通道的突变。强直性肌营养不良是由于染色体19q13.3上编码推定的丝氨酸-苏氨酸蛋白激酶的基因的38个非翻译区中的CTG重复扩增，而先天性肌强直是由于编码骨骼肌氯离子通道（CLCN 1）的基因突变。所有导致先天性副肌强直、高钾性周期性麻痹和钾加重肌强直的骨骼肌钠通道突变均导致功能获得性缺陷，由此突变通道通过比正常通道更多的Na电流。在大多数情况下，这是由于突变钠通道的快速失活受损。正常情况下，肌肉膜上的电压门控钠通道在去极化过程中短暂开放，然后接近快速失活状态，从而限制动作电位的持续时间并启动复极化。在钠通道失活期间，肌肉膜不可兴奋。这个“不应期”持续到钠通道从失活中恢复。因此，钠通道的失活限制了兴奋性，并因此限制了动作电位沿着肌膜的放电速率。在骨骼肌的钠通道疾病中，突变型钠通道的失活受损导致通过肌膜的Na内流增加，从而引起轻微去极化伴过度兴奋（肌强直）或持续去极化伴不兴奋（轻瘫）。在大多数先天性副肌强直的情况下，突变型钠通道表现出通道门控异常，不仅涉及快速失活速率的减慢，而且还涉及失活恢复速率的加速。因此，突变的钠通道在失活状态下花费的时间更少，导致持续的内向钠电流，促进过度的膜去极化和肌强直电位的异常序列。麻醉和手术对骨骼肌钠离子通道病患者有特殊的风险。手术中的大多数并发症与肌强直的形成直接相关，肌强直可能使麻醉过程复杂化并且难以消除。许多经历这些并发症的患者对某些药物表现出极端敏感性，对其他药物表现出异常反应。据报道，在麻醉诱导和维持期间，肌钠通道病患者会出现严重甚至危及生命的并发症。麻醉诱导期间可能发生的最引人注目的并发症之一与使用去极化神经肌肉阻滞剂（例如琥珀胆碱）有关。由于其对骨骼肌的直接去极化作用，去极化神经肌肉阻滞剂如琥珀胆碱可诱发全身性肌强直。这可能导致气管插管和通气困难，特别是当肌强直反应导致强烈的咬肌僵硬时。麻醉剂，如thiamy。英格兰;电子邮件：jengla@lsuhsc.edu
Paramyotonia congenita is an autosomal dominant muscle disease that is characterized by cold-induced and exercise-induced myotonia. Paramyotonia congenita is one of a group of muscle diseases that are due to missense mutations in the gene that codes for the skeletal muscle sodium channel a-subunit (SCN4A). All of these so-called muscle “sodium channelopathies” share an abnormality of muscle membrane excitability that can be variably expressed as myotonia or weakness. Three of these allelic disorders characteristically exhibit myotonia and have been named the “sodium channel myotonias.” Currently, the known sodium channel myotonias are paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia. To avoid misunderstanding, it is worth pointing out that neither myotonic dystrophy nor myotonia congenita is due to mutations of muscle sodium channels. Myotonic dystrophy is due to an expanded CTG repeat in the 38 untranslated region of the gene encoding the putative serine–threonine protein kinase on chromosome 19q13.3, and myotonia congenita is due to mutations of the gene coding for the skeletal muscle chloride channel (CLCN1). All the mutations of the skeletal muscle sodium channel that cause paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia result in gain-of-function defects, whereby the mutant channels pass more Na current than normal. In most cases, this is due to an impairment of fast inactivation of the mutant sodium channels. Normally, voltage-gated sodium channels in muscle membrane open briefly during depolarization and then close to a fast inactivated state, thereby limiting the duration of action potentials and initiating repolarization. During the period when sodium channels are inactivated, the muscle membrane is inexcitable. This “refractory period” lasts until the sodium channels recover from inactivation. Thus, inactivation of sodium channels limits the excitability and, consequently, the firing rate of action potentials along the muscle membrane. In the sodium channel diseases of skeletal muscle, the impaired inactivation of mutant sodium channels results in an increased Na influx through the muscle membrane, causing either slight depolarization with hyperexcitability (myotonia) or sustained depolarization with inexcitability (paresis). In most cases of paramyotonia congenita, the mutant sodium channels exhibit abnormalities of channel gating that involve not only a slowing of the rate of fast inactivation but also an acceleration of the rate of recovery from inactivation. Thus, the mutant sodium channels spend less time in the inactivated state, resulting in a persistent inward Na current that promotes excessive membrane depolarization and abnormal trains of myotonic potentials. Anesthesia and surgery pose special risks for patients with sodium channelopathies of skeletal muscle. Most complications during surgery are related directly to the precipitation of myotonia, which may complicate the course of anesthesia and be difficult to abolish. Many patients who experience these complications display extreme sensitivity to some drugs and abnormal reactions to others. Severe and even life-threatening complications have been reported in patients with muscle sodium channelopathies during induction and maintenance of anesthesia. One of the most striking complications that can occur during induction of anesthesia is associated with the use of depolarizing neuromuscular blocking agents such as succinylcholine. Because of their direct depolarizing effect upon skeletal muscle, depolarizing neuromuscular blocking agents such as succinylcholine can precipitate generalized myotonia. This can result in difficulties in tracheal intubation and ventilation, especially when the myotonic response results in intense masseter muscle rigidity. Anesthetics such as thiamyCorrespondence to: J.D. England; e-mail: jengla@lsuhsc.edu
异丙酚的全身麻醉效力及其对静水压的依赖性。
影响因子：
8.8
作者：
Tonner,PH;Poppers,DM;Miller,KW
通讯作者：
Miller,KW
影响因子：
8.8
作者：
Rehberg, B;Duch, DS
通讯作者：
Duch, DS