Department of Pharmacology, University of California, Davis, CA, 95616, USA.
Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KY, 40202, USA.
Sci Rep. 2017 Oct 25;7(1):14058. doi: 10.1038/s41598-017-14565-9.
Large-conductance Ca-activated potassium (BK) channels are key determinants of vascular smooth muscle excitability. Impaired BK channel function through remodeling of BK β1 expression and function contributes to vascular complications in animal models of diabetes. Yet, whether similar alterations occur in native vascular smooth muscle from humans with type 2 diabetes is unclear. In this study, we evaluated BK function in vascular smooth muscle from small resistance adipose arteries of non-diabetic and clinically diagnosed type 2 diabetic patients. We found that BK channel activity opposes pressure-induced constriction in human small resistance adipose arteries, and this is compromised in arteries from diabetic patients. Consistent with impairment of BK channel function, the amplitude and frequency of spontaneous BK currents, but not Ca sparks were lower in cells from diabetic patients. BK channels in diabetic cells exhibited reduced Ca sensitivity, single-channel open probability and tamoxifen sensitivity. These effects were associated with decreased functional coupling between BK α and β1 subunits, but no change in total protein abundance. Overall, results suggest impairment in BK channel function in vascular smooth muscle from diabetic patients through unique mechanisms, which may contribute to vascular complications in humans with type 2 diabetes.
大电导钙激活钾（BK）通道是血管平滑肌兴奋性的关键决定因素。通过重塑 BKβ1 的表达和功能，BK 通道功能受损导致糖尿病动物模型中的血管并发症。然而，在 2 型糖尿病患者的天然血管平滑肌中是否发生类似的改变尚不清楚。在这项研究中，我们评估了来自非糖尿病和临床诊断为 2 型糖尿病患者的小阻力脂肪动脉的血管平滑肌中的 BK 功能。我们发现，BK 通道活性在人小阻力脂肪动脉中对抗压力诱导的收缩，而在糖尿病患者的动脉中则受到损害。与 BK 通道功能受损一致，糖尿病患者细胞中的自发 BK 电流幅度和频率降低，但 Ca 火花没有降低。糖尿病细胞中的 BK 通道显示 Ca 敏感性降低、单通道开放概率降低和他莫昔芬敏感性降低。这些影响与 BKα 和β1 亚基之间的功能偶联减少有关，但总蛋白丰度没有变化。总的来说，结果表明，糖尿病患者血管平滑肌中的 BK 通道功能受损是通过独特的机制发生的，这可能导致 2 型糖尿病患者的血管并发症。
