From the Department of Physiology and Pharmacology, Robarts Research Institute (M.S., S.F., S.E.B., D.G.W.), University of Western Ontario, London, Canada.
Department of Neuroscience, Translational Neurobiology, University of Copenhagen, Denmark (B.O.H.).
Arterioscler Thromb Vasc Biol. 2019 Jun;39(6):1072-1087. doi: 10.1161/ATVBAHA.119.312493.
Objective- Inward rectifying K (K) channels are present in cerebral arterial smooth muscle and endothelial cells, a tandem arrangement suggestive of a dynamic yet undiscovered role for this channel. This study defined whether distinct pools of cerebral arterial K channels were uniquely modulated by membrane lipids and hemodynamic stimuli. Approach and Results- A Ba-sensitive K current was isolated in smooth muscle and endothelial cells of rat cerebral arteries; molecular analyses subsequently confirmed K2.1/K2.2 mRNA and protein expression in both cells. Patch-clamp electrophysiology next demonstrated that each population of K channels was sensitive to key membrane lipids and hemodynamic stimuli. In this regard, endothelial K was sensitive to phosphatidylinositol 4,5-bisphosphate content, with depletion impairing the ability of laminar shear stress to activate this channel pool. In contrast, smooth muscle K was sensitive to membrane cholesterol content, with sequestration blocking the ability of pressure to inhibit channel activity. The idea that membrane lipids help confer shear stress and pressure sensitivity of K channels was confirmed in intact arteries using myography. Virtual models integrating structural/electrical observations reconceptualized K as a dynamic regulator of membrane potential working in concert with other currents to set basal tone across a range of shear stresses and intravascular pressures. Conclusions- The data show for the first time that specific membrane lipid-K interactions enable unique channel populations to sense hemodynamic stimuli and drive vasomotor responses to set basal perfusion in the cerebral circulation.
内向整流钾 (K) 通道存在于脑动脉平滑肌和内皮细胞中，这种串联排列提示该通道具有动态但尚未被发现的作用。本研究旨在确定脑动脉 K 通道的不同池是否被独特地由膜脂质和血液动力学刺激所调节。
在大鼠脑动脉的平滑肌和内皮细胞中分离出 Ba 敏感的 K 电流；随后的分子分析证实了这两种细胞中 K2.1/K2.2 mRNA 和蛋白的表达。膜片钳电生理学进一步表明，两种细胞群体的 K 通道都对关键膜脂质和血液动力学刺激敏感。在这方面，内皮 K 对磷脂酰肌醇 4,5-二磷酸含量敏感，其耗竭会损害层流剪切力激活该通道池的能力。相比之下，平滑肌 K 对膜胆固醇含量敏感，胆固醇隔离会阻止压力抑制通道活性的能力。使用血管造影术，用膜脂质有助于赋予 K 通道剪切力和压力敏感性的虚拟模型证实了这一观点。整合结构/电观察的虚拟模型将 K 重新概念化为一种动态的膜电位调节剂，与其他电流协同作用，在一系列剪切力和血管内压力下设定基础张力。
数据首次表明，特定的膜脂质-K 相互作用使特定的通道群体能够感知血液动力学刺激，并驱动血管运动反应，以在脑循环中设定基础灌注。
