McCrossan Zoe A, Roepke Torsten K, Lewis Anthony, Panaghie Gianina, Abbott Geoffrey W
Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
J Membr Biol. 2009 Mar;228(1):1-14. doi: 10.1007/s00232-009-9154-8. Epub 2009 Feb 14.
Kv2.1 is a voltage-gated potassium (Kv) channel alpha-subunit expressed in mammalian heart and brain. MinK-related peptides (MiRPs), encoded by KCNE genes, are single-transmembrane domain ancillary subunits that form complexes with Kv channel alpha-subunits to modify their function. Mutations in human MinK (KCNE1) and MiRP1 (KCNE2) are associated with inherited and acquired forms of long QT syndrome (LQTS). Here, coimmunoprecipitations from rat heart tissue suggested that both MinK and MiRP1 form native cardiac complexes with Kv2.1. In whole-cell voltage-clamp studies of subunits expressed in CHO cells, rat MinK and MiRP1 reduced Kv2.1 current density three- and twofold, respectively; slowed Kv2.1 activation (at +60 mV) two- and threefold, respectively; and slowed Kv2.1 deactivation less than twofold. Human MinK slowed Kv2.1 activation 25%, while human MiRP1 slowed Kv2.1 activation and deactivation twofold. Inherited mutations in human MinK and MiRP1, previously associated with LQTS, were also evaluated. D76N-MinK and S74L-MinK reduced Kv2.1 current density (threefold and 40%, respectively) and slowed deactivation (60% and 80%, respectively). Compared to wild-type human MiRP1-Kv2.1 complexes, channels formed with M54T- or I57T-MiRP1 showed greatly slowed activation (tenfold and fivefold, respectively). The data broaden the potential roles of MinK and MiRP1 in cardiac physiology and support the possibility that inherited mutations in either subunit could contribute to cardiac arrhythmia by multiple mechanisms.
Kv2.1是一种电压门控钾（Kv）通道α亚基，在哺乳动物的心脏和大脑中表达。由KCNE基因编码的MinK相关肽（MiRPs）是单跨膜结构域辅助亚基，它们与Kv通道α亚基形成复合物以改变其功能。人类MinK（KCNE1）和MiRP1（KCNE2）的突变与遗传性和获得性长QT综合征（LQTS）有关。在这里，来自大鼠心脏组织的免疫共沉淀表明，MinK和MiRP1都与Kv2.1形成天然心脏复合物。在CHO细胞中表达的亚基的全细胞电压钳研究中，大鼠MinK和MiRP1分别使Kv2.1电流密度降低了三倍和两倍；使Kv2.1激活（在+60 mV时）分别减慢了两倍和三倍；使Kv2.1失活减慢不到两倍。人类MinK使Kv2.1激活减慢25%，而人类MiRP1使Kv2.1激活和失活减慢两倍。还评估了先前与LQTS相关的人类MinK和MiRP1的遗传性突变。D76N-MinK和S74L-MinK降低了Kv2.1电流密度（分别为三倍和40%）并减慢了失活（分别为60%和80%）。与野生型人类MiRP1-Kv2.1复合物相比，由M54T-或I57T-MiRP1形成的通道显示激活大大减慢（分别为十倍和五倍）。这些数据拓宽了MinK和MiRP1在心脏生理学中的潜在作用，并支持任一亚基的遗传性突变可能通过多种机制导致心律失常的可能性。
