Leo M Dennis, Zhai Xue, Muralidharan Padmapriya, Kuruvilla Korah P, Bulley Simon, Boop Frederick A, Jaggar Jonathan H
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Sci Signal. 2017 May 9;10(478):eaah5417. doi: 10.1126/scisignal.aah5417.
Membrane depolarization of smooth muscle cells (myocytes) in the small arteries that regulate regional organ blood flow leads to vasoconstriction. Membrane depolarization also activates large-conductance calcium (Ca)-activated potassium (BK) channels, which limits Ca channel activity that promotes vasoconstriction, thus leading to vasodilation. We showed that in human and rat arterial myocytes, membrane depolarization rapidly increased the cell surface abundance of auxiliary BK β1 subunits but not that of the pore-forming BKα channels. Membrane depolarization stimulated voltage-dependent Ca channels, leading to Ca influx and the activation of Rho kinase (ROCK) 1 and 2. ROCK1/2-mediated activation of Rab11A promoted the delivery of β1 subunits to the plasma membrane by Rab11A-positive recycling endosomes. These additional β1 subunits associated with BKα channels already at the plasma membrane, leading to an increase in apparent Ca sensitivity and activation of the channels in pressurized arterial myocytes and vasodilation. Thus, membrane depolarization activates BK channels through stimulation of ROCK- and Rab11A-dependent trafficking of β1 subunits to the surface of arterial myocytes.
调节局部器官血流的小动脉平滑肌细胞（肌细胞）的膜去极化会导致血管收缩。膜去极化还会激活大电导钙（Ca）激活钾（BK）通道，该通道会限制促进血管收缩的钙通道活性，从而导致血管舒张。我们发现，在人和大鼠动脉肌细胞中，膜去极化会迅速增加辅助BKβ1亚基的细胞表面丰度，但不会增加形成孔道的BKα通道的丰度。膜去极化刺激电压依赖性钙通道，导致钙内流以及Rho激酶（ROCK）1和2的激活。ROCK1/2介导的Rab11A激活促进了Rab11A阳性循环内体将β1亚基递送至质膜。这些额外的β1亚基与已经位于质膜的BKα通道结合，导致加压动脉肌细胞中通道的表观钙敏感性增加和通道激活，进而引起血管舒张。因此，膜去极化通过刺激ROCK和Rab11A依赖性的β1亚基向动脉肌细胞表面的转运来激活BK通道。
