Scholz Nicole, Guan Chonglin, Nieberler Matthias, Grotemeyer Alexander, Maiellaro Isabella, Gao Shiqiang, Beck Sebastian, Pawlak Matthias, Sauer Markus, Asan Esther, Rothemund Sven, Winkler Jana, Prömel Simone, Nagel Georg, Langenhan Tobias, Kittel Robert J
Department of Neurophysiology, Institute of Physiology, University of Würzburg, Würzburg, Germany.
Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig, Germany.
Elife. 2017 Aug 8;6:e28360. doi: 10.7554/eLife.28360.
Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. Here we show that the aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response.
粘附型G蛋白偶联受体（aGPCRs）是一个在人类中有30多个成员的大分子家族，在器官发育、脑功能中发挥作用并调控免疫反应。相应地，这个受体家族与多种人类疾病相关。尽管aGPCRs的作用机制完全未知，但已有研究表明它们具有机械感觉特性。在这里，我们展示了aGPCR Latrophilin/dCIRL通过调节离子型受体电流（细胞机械感觉的起始步骤）在机械感觉神经元中发挥作用。这个过程取决于受体延伸胞外域的长度和拴系激动剂，但不依赖于其自身蛋白酶解作用（aGPCR家族的一个特征性生化特性）。在细胞内，dCIRL在机械激活时降低cAMP水平，从而特异性地增加神经元的机械敏感性。这些结果提供了直接证据，表明aGPCR dCIRL作为一种分子传感器和信号转导器，能够检测机械刺激并将其转化为代谢型反应。
