Hayward L J, Sandoval G M, Cannon S C
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
Neurology. 1999 Apr 22;52(7):1447-53. doi: 10.1212/wnl.52.7.1447.
To evaluate the effects of missense mutations within the skeletal muscle sodium (Na) channel on slow inactivation (SI) in periodic paralysis and related myotonic disorders.
Na channel mutations in hyperkalemic periodic paralysis and the nondystrophic myotonias interfere with the normally rapid inactivation of muscle Na currents following an action potential. This defect causes persistent inward Na currents that produce muscle depolarization, myotonia, or onset of weakness. Distinct from fast inactivation is the process called SI, which limits availability of Na channels on a time scale of seconds to minutes, thereby influencing muscle excitability.
Human Na channel cDNAs containing mutations associated with paralytic and nonparalytic phenotypes were transiently expressed in human embryonic kidney cells for whole-cell Na current recording. Extent of SI over a range of conditioning voltages (-120 to +20 mV) was defined as the fraction of Na current that failed to recover within 20 ms at - 100 mV. The time course of entry to SI at -30 mV was measured using a conditioning pulse duration of 20 ms to 60 seconds. Recovery from SI at -100 mV was assessed over 20 ms to 10 seconds.
The two most common hyperkalemic periodic paralysis (HyperPP) mutations responsible for episodic attacks of weakness or paralysis, T704M and M1592V, showed clearly impaired SI, as we and others have observed previously for the rat homologs of these mutations. In addition, a new paralysis-associated mutant, I693T, with cold-induced weakness, exhibited a comparable defect in SI. However, SI remained intact for both the HyperPP/paramyotonia congenita (PMC) mutant, A1156T, and the nonparalytic potassium-aggravated myotonia (PAM) mutant, V1589M.
SI is defective in a subset of mutant Na channels associated with episodic weakness (HyperPP or PMC) but remains intact for mutants studied so far that cause myotonia without weakness (PAM).
评估骨骼肌钠（Na）通道错义突变对周期性麻痹及相关肌强直疾病中慢失活（SI）的影响。
高钾性周期性麻痹和非营养不良性肌强直中的钠通道突变会干扰动作电位后肌肉钠电流正常的快速失活。这一缺陷会导致持续性内向钠电流，从而引起肌肉去极化、肌强直或肌无力发作。与快速失活不同的是所谓的慢失活过程，它在数秒到数分钟的时间尺度上限制钠通道的可用性，进而影响肌肉兴奋性。
将含有与麻痹性和非麻痹性表型相关突变的人钠通道cDNA瞬时转染至人胚肾细胞中，用于全细胞钠电流记录。在一系列预处理电压（-120至+20 mV）范围内，慢失活程度定义为在-100 mV时20 ms内未能恢复的钠电流分数。使用20 ms至60秒的预处理脉冲持续时间测量在-30 mV时进入慢失活的时间进程。评估在-100 mV时从慢失活状态恢复20 ms至10秒的情况。
导致发作性肌无力或麻痹的两种最常见的高钾性周期性麻痹（HyperPP）突变，T704M和M1592V，表现出明显受损的慢失活，正如我们和其他人之前在这些突变的大鼠同源物中所观察到的那样。此外，一个新的与麻痹相关的突变体I693T，伴有冷诱导肌无力，在慢失活方面表现出类似的缺陷。然而，对于HyperPP/先天性副肌强直（PMC）突变体A1156T和非麻痹性钾加重性肌强直（PAM）突变体V1589M，慢失活均保持完整。
与发作性肌无力（HyperPP或PMC）相关的一部分突变钠通道存在慢失活缺陷，但对于目前研究的导致无肌无力的肌强直（PAM）的突变体，慢失活保持完整。
