Rhee Sung W, Rusch Nancy J
Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Microcirculation. 2018 Jan;25(1). doi: 10.1111/micc.12425.
Voltage-gated K (K ) channels are major determinants of membrane potential in vascular smooth muscle cells (VSMCs) and regulate the diameter of small cerebral arteries and arterioles. However, the intracellular structures that govern the expression and function of vascular K channels are poorly understood. Scaffolding proteins including postsynaptic density 95 (PSD95) recently were identified in rat cerebral VSMCs. Primarily characterized in neurons, the PSD95 scaffold has more than 50 known binding partners, and it can mediate macromolecular signaling between cell-surface receptors and ion channels. In cerebral arteries, Shaker-type K 1 channels appear to associate with the PSD95 molecular scaffold, and PSD95 is required for the normal expression and vasodilator influence of members of this K channel gene family. Furthermore, recent findings suggest that the β1-subtype adrenergic receptor is expressed in cerebral VSMCs and forms a functional vasodilator complex with K 1 channels on the PSD95 scaffold. Activation of β1-subtype adrenergic receptors in VSMCs enables protein kinase A-dependent phosphorylation and opening of K 1 channels in the PSD95 complex; the subsequent K efflux mediates membrane hyperpolarization and vasodilation of small cerebral arteries. Early evidence from other studies suggests that other families of K channels and scaffolding proteins are expressed in VSMCs. Future investigations into these macromolecular complexes that modulate the expression and function of K channels may reveal unknown signaling cascades that regulate VSMC excitability and provide novel targets for ion channel-based medications to optimize vascular tone.
电压门控钾（K⁺）通道是血管平滑肌细胞（VSMCs）膜电位的主要决定因素，并调节大脑小动脉和小动脉的直径。然而，调控血管钾通道表达和功能的细胞内结构却鲜为人知。最近在大鼠脑VSMCs中发现了包括突触后致密蛋白95（PSD95）在内的支架蛋白。PSD95支架主要在神经元中得到表征，已知有50多个结合伴侣，它可以介导细胞表面受体与离子通道之间的大分子信号传导。在脑动脉中，Shaker型K⁺通道似乎与PSD95分子支架相关联，并且PSD95是该钾通道基因家族成员正常表达和血管舒张作用所必需的。此外，最近的研究结果表明，β1-肾上腺素能受体亚型在脑VSMCs中表达，并与PSD95支架上的K⁺通道形成功能性血管舒张复合物。VSMCs中β1-肾上腺素能受体亚型的激活使蛋白激酶A依赖性磷酸化并打开PSD95复合物中的K⁺通道；随后的K⁺外流介导膜超极化和大脑小动脉的血管舒张。其他研究的早期证据表明，其他钾通道家族和支架蛋白在VSMCs中表达。未来对这些调节钾通道表达和功能的大分子复合物的研究可能会揭示调节VSMC兴奋性的未知信号级联反应，并为基于离子通道的药物提供新的靶点，以优化血管张力。
