Department of Medicine, Center for Translational Medicine and Division of Pulmonary, Allergy and Critical Care Medicine; and Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
Am J Physiol Lung Cell Mol Physiol. 2019 May 1;316(5):L894-L902. doi: 10.1152/ajplung.00426.2018. Epub 2019 Feb 6.
Ovarian cancer G protein-coupled receptor 1 (OGR1) is a recently deorphanized G protein-coupled receptor shown to signal in response to low extracellular pH (↓pH) or certain benzodiazepines. The pleiotropic nature of OGR1 signaling in human airway smooth muscle (HASM) cells suggests that OGR1 is a potential therapeutic target for the management of obstructive lung diseases. However, the basic pharmacological and regulatory features of OGR1 remain poorly understood. We employed model systems of heterologously expressed [human embryonic kidney 293 (HEK293) cells] or endogenous (HASM) OGR1 to assess changes in expression, subcellular localization, and signaling capabilities following acute or chronic treatment with ↓pH or the benzodiazepines lorazepam and sulazepam. In HEK293 cells expressing OGR1, treatment with ↓pH and/or lorazepam, but not sulazepam, caused rapid OGR1 internalization. In HASM cells, acute treatment with ↓pH or benzodiazepines did not alter abundance of OGR1 mRNA; however, significant downregulation was observed following chronic treatment. Acute and chronic pretreatment of HASM cells with sulazepam or lorazepam resulted in receptor desensitization as demonstrated by reduced phosphorylation of vasodilator-stimulated phosphoprotein (VASP) or p42/p44 upon rechallenge. Acid (acute but not chronic) pretreatment of HASM cells induced desensitization of OGR1-mediated VASP (but not p42/p44) phosphorylation. In contrast to a recent study reporting OGR1 upregulation and sensitization in cardiac tissue subject to ischemic/acidic insult, chronic OGR1 activation in multiple model systems did not increase OGR1 expression or signaling capacity. The ability to induce OGR1 internalization and desensitization was activator dependent, reflecting the ability of different activators to induce specific receptor confirmations and engagement of specific heterotrimeric G proteins.
卵巢癌 G 蛋白偶联受体 1（OGR1）是一种最近被重新定义的 G 蛋白偶联受体，它被证明可以对外界低 pH 值（↓pH）或某些苯二氮䓬类药物做出信号反应。OGR1 在人呼吸道平滑肌（HASM）细胞中的多效性信号表明，OGR1 可能成为治疗阻塞性肺部疾病的潜在治疗靶点。然而，OGR1 的基本药理学和调节特征仍知之甚少。我们采用异源表达[人胚肾 293（HEK293）细胞]或内源性（HASM）OGR1 的模型系统，评估在急性或慢性处理↓pH 值或苯二氮䓬类药物劳拉西泮和舒拉西泮后，OGR1 的表达、亚细胞定位和信号转导能力的变化。在表达 OGR1 的 HEK293 细胞中，↓pH 值和/或劳拉西泮处理而非舒拉西泮处理会导致 OGR1 快速内化。在 HASM 细胞中，急性处理↓pH 值或苯二氮䓬类药物不会改变 OGR1 mRNA 的丰度；然而，在慢性处理后观察到明显的下调。HASM 细胞的急性和慢性预处理用舒拉西泮或劳拉西泮导致受体脱敏，表现为再刺激时血管扩张刺激磷蛋白（VASP）或 p42/p44 的磷酸化减少。酸（急性而非慢性）预处理 HASM 细胞诱导 OGR1 介导的 VASP（而非 p42/p44）磷酸化脱敏。与最近的一项研究报告称，在经历缺血/酸性损伤的心脏组织中 OGR1 上调和致敏相反，在多个模型系统中慢性 OGR1 激活并没有增加 OGR1 的表达或信号转导能力。诱导 OGR1 内化和脱敏的能力取决于激活剂，反映了不同激活剂诱导特定受体构象和特定异三聚体 G 蛋白结合的能力。
