Parathyroid hormone (PTH) binds to a family B G protein coupled receptor, parathyroid hormone 1 receptor (PTH1R). One of its functions is to regulate Ca²⁺ homeostasis in bone remodeling, during which Ca²⁺ can reach up to 40 mM. A truncated version of PTH, PTH(1–34), can fully activate PTH1R and has been used for osteoporosis treatments. Here, we used fluorescence anisotropy to examine the binding of PTH(1–34) to PTH1R purified in nanodiscs (PTH1R-ND) and found that the affinity increases 5-fold in the presence of 15 mM Ca²⁺. However, PTHrP(1–36), another truncated endogenous agonist for PTH1R, does not show this Ca²⁺ effect. Mutations of Glu19 and Glu22 in PTH(1–34) that are not conserved in PTHrP(1–36) largely abolished the Ca²⁺ effect. The results support that PTH(1–34) not only activates PTH1R but also uniquely senses Ca²⁺. This dual function of a peptide hormone is a novel observation that couples changes in extracellular environment with endocrine signaling. Understanding this can potentially reveal the complex role of PTH signaling in bone remodeling and improve the PTH(1–34) treatment for osteoporosis.

中文翻译：

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甲状旁腺激素通过与 B 家族 GPCR 甲状旁腺激素 1 受体结合来感知细胞外钙以调节内分泌信号传导

甲状旁腺激素 (PTH) 与 BG 蛋白偶联受体家族、甲状旁腺激素 1 受体 (PTH1R) 结合。其功能之一是调节骨重塑过程中的Ca ²⁺稳态，期间Ca ²⁺可达40 mM。PTH 的截短版本 PTH(1–34) 可以完全激活 PTH1R，并已用于骨质疏松症的治疗。^{在这里，我们使用荧光各向异性来检查 PTH(1–34) 与纳米圆盘 (PTH1R-ND) 中纯化的 PTH1R 的结合，发现在 15 mM Ca 2+}存在下亲和力增加 5 倍。然而，另一种截短的 PTH1R 内源性激动剂 PTHrP(1–36) 并不显示这种 Ca ²⁺效应。PTH(1-34) 中 Glu19 和 Glu22 的突变（在 PTHrP(1-36) 中不保守）很大程度上消除了 Ca ²⁺效应。结果支持PTH(1–34)不仅激活PTH1R而且还独特地感知Ca ²⁺。肽激素的这种双重功能是一种新颖的观察，它将细胞外环境的变化与内分泌信号传导结合起来。了解这一点可能会揭示 PTH 信号在骨重塑中的复杂作用，并改善 PTH(1-34) 对骨质疏松症的治疗。