Hayward L J, Brown R H, Cannon S C
Department of Neurology, Massachusetts General Hospital, Boston 02114, USA.
J Gen Physiol. 1996 May;107(5):559-76. doi: 10.1085/jgp.107.5.559.
Missense mutations in the skeletal muscle Na+ channel alpha subunit occur in several heritable forms of myotonia and periodic paralysis. Distinct phenotypes arise from mutations at two sites within the III-IV cytoplasmic loop: myotonia without weakness due to substitutions at glycine 1306, and myotonia plus weakness caused by a mutation at threonine 1313. Heterologous expression in HEK cells showed that substitutions at either site disrupted inactivation, as reflected by slower inactivation rates, shifts in steady-state inactivation, and larger persistent Na+ currents. For T1313M, however, the changes were an order of magnitude larger than any of three substitutions at G1306, and recovery from inactivation was hastened as well. Model simulations demonstrate that these functional difference have distinct phenotypic consequences. In particular, a large persistent Na+ current predisposes to paralysis due to depolarization-induced block of action potential generation.
骨骼肌钠通道α亚基的错义突变存在于几种遗传性肌强直和周期性麻痹中。III-IV胞质环内两个位点的突变产生了不同的表型：由于甘氨酸1306处的替代导致无肌无力的肌强直，以及由苏氨酸1313处的突变引起的肌强直加肌无力。在HEK细胞中的异源表达表明，任何一个位点的替代都会破坏失活，这表现为失活速率减慢、稳态失活的改变以及更大的持续性钠电流。然而，对于T1313M，这些变化比G1306处的三个替代中的任何一个都大一个数量级，并且失活恢复也加快了。模型模拟表明，这些功能差异具有不同的表型后果。特别是，大的持续性钠电流易导致因去极化诱导的动作电位产生阻滞而引起的麻痹。
