O'Malley Dervla, Irving Andrew J, Harvey Jenni
Neuroscience Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
FASEB J. 2005 Nov;19(13):1917-9. doi: 10.1096/fj.05-4166fje. Epub 2005 Sep 15.
Phosphoinositide 3-kinase (PI3-kinase) has been shown to link leptin receptor activation to stimulation of large conductance Ca2+-activated K+ (BK) channels and subsequent inhibition of hippocampal epileptiform-like activity. However, the downstream targets of PI3-kinase in this action of leptin are unknown. Here we show that BK channel activation by leptin is dependent on the actin cytoskeleton, as it is prevented by actin filament stabilization and mimicked by actin disruption. Fluorescent labeling of polymerized actin filaments revealed that leptin promotes the rapid rearrangement of actin filaments via activation of PI 3-kinase; an action paralleled by discrete increases in PtdIns(3,4,5)P3 immunoreactivity in close proximity to BK channels. After leptin exposure, there was also an actin-dependent increase in the association of BK channel immunoreactivity with synaptic markers. These data are consistent with the notion that leptin activates BK channels via PI 3-kinase-dependent reorganization of actin filaments and subsequent clustering of BK channels at synapses.
磷酸肌醇3激酶（PI3激酶）已被证明可将瘦素受体激活与大电导钙激活钾（BK）通道的刺激以及随后对海马癫痫样活动的抑制联系起来。然而，瘦素这一作用中PI3激酶的下游靶点尚不清楚。在此我们表明，瘦素对BK通道的激活依赖于肌动蛋白细胞骨架，因为肌动蛋白丝的稳定可阻止这一过程，而肌动蛋白的破坏则可模拟这一过程。聚合肌动蛋白丝的荧光标记显示，瘦素通过激活PI 3激酶促进肌动蛋白丝的快速重排；这一作用与BK通道附近磷脂酰肌醇（3,4,5）三磷酸（PtdIns(3,4,5)P3）免疫反应性的离散增加相平行。瘦素暴露后，BK通道免疫反应性与突触标记物的结合也有肌动蛋白依赖性增加。这些数据与以下观点一致，即瘦素通过PI 3激酶依赖性的肌动蛋白丝重组以及随后BK通道在突触处的聚集来激活BK通道。
