Department of Cell and Systems Physiology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, 807-8555, Japan.
Department of Psychology, Fukuoka Prefectural University School of Human and Social Sciences, 4395 Ita, Tagawa, Fukuoka, 825-8585, Japan.
Pflugers Arch. 2020 Jul;472(7):911-922. doi: 10.1007/s00424-020-02403-3. Epub 2020 May 29.
TWIK-related acid-sensitive K (TASK) channels contribute to the resting membrane potential in various kinds of cells, such as brain neurons, smooth muscle cells, and endocrine cells. Loss-of-function mutations at multiple sites in the KCNK3 gene encoding for TASK1 channels are one of the causes of pulmonary arterial hypertension in humans, whereas a mutation at only one site is reported for TASK3 channels, resulting in a syndrome of mental retardation, hypotonia, and facial dysmorphism. TASK channels are subject to regulation by G protein-coupled receptors (GPCRs). Two mechanisms have been proposed for the GPCR-mediated inhibition of TASK channels: a change in gating and channel endocytosis. The most feasible mechanism for altered gating is diacylglycerol binding to a site in the C-terminus, which is shared by TASK1 and TASK3. The inhibition of channel function by endocytosis requires the presence of a tyrosine residue subjected to phosphorylation by the non-receptor tyrosine kinase Src and a dileucine motif in the C-terminus of TASK1. Therefore, homomeric TASK1 and heteromeric TASK1-TASK3 channels, but not homomeric TASK3, are internalized by GPCR stimulation. Tyrosine phosphorylation by Src is expected to result in a conformational change in the C-terminus, allowing for AP-2, an adaptor protein for clathrin, to bind to the dileucine motif. It is likely that a raft membrane domain is a platform where TASK1 is located and the signaling molecules protein kinase C, Pyk2, and Src are recruited in sequence in response to GPCR stimulation.
TWIK 相关酸敏感钾 (TASK) 通道有助于各种细胞（如脑神经元、平滑肌细胞和内分泌细胞）的静息膜电位。编码 TASK1 通道的 KCNK3 基因多个位点的功能丧失突变是人类肺动脉高压的原因之一，而 TASK3 通道仅一个位点的突变会导致智力迟钝、张力减退和面部畸形综合征。TASK 通道受 G 蛋白偶联受体 (GPCR) 的调节。已经提出了两种 GPCR 介导的 TASK 通道抑制机制：门控变化和通道内吞作用。门控变化的最可行机制是二酰基甘油与 C 末端的一个位点结合，该位点由 TASK1 和 TASK3 共享。内吞作用抑制通道功能需要存在一个酪氨酸残基，该残基受非受体酪氨酸激酶Src 的磷酸化作用，以及 TASK1 C 末端的亮氨酸二肽基序。因此，同型 TASK1 和异型 TASK1-TASK3 通道，但不是同型 TASK3 通道，可被 GPCR 刺激内化。Src 的酪氨酸磷酸化预计会导致 C 末端构象发生变化，从而允许衔接蛋白 AP-2 与亮氨酸二肽基序结合。很可能是筏状膜域是 TASK1 所在的平台，并且信号分子蛋白激酶 C、Pyk2 和 Src 依次被募集，以响应 GPCR 刺激。
