Roszko Kelly L, Bi Ruiye D, Mannstadt Michael
Endocrine Unit, Massachusetts General Hospital and Harvard Medical School Boston, MA, USA.
Front Physiol. 2016 Oct 18;7:458. doi: 10.3389/fphys.2016.00458. eCollection 2016.
Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR), expressed on the surface of parathyroid cells. In response to low ionized calcium, the parathyroids increase secretion of parathyroid hormone (PTH) which increases serum calcium. The CASR is also highly expressed in the kidneys, where it regulates the reabsorption of calcium from the primary filtrate. Autosomal dominant hypocalcemia (ADH) type 1 is caused by heterozygous activating mutations in the CASR which increase the sensitivity of the CASR to extracellular ionized calcium. Consequently, PTH synthesis and secretion are suppressed at normal ionized calcium concentrations. Patients present with hypocalcemia, hyperphosphatemia, low magnesium levels, and low or low-normal levels of PTH. Urinary calcium excretion is typically increased due to the decrease in circulating PTH concentrations and by the activation of the renal tubular CASR. Therapeutic attempts using CASR antagonists (calcilytics) to treat ADH are currently under investigation. Recently, heterozygous mutations in the alpha subunit of the G protein G11 (Gα11) have been identified in patients with ADH, and this has been classified as ADH type 2. ADH2 mutations lead to a gain-of-function of Gα11, a key mediator of CASR signaling. Therefore, the mechanism of hypocalcemia appears similar to that of activating mutations in the CASR, namely an increase in the sensitivity of parathyroid cells to extracellular ionized calcium. Studies of activating mutations in the CASR and gain-of-function mutations in Gα11 can help define new drug targets and improve medical management of patients with ADH types 1 and 2.
细胞外钙对生命至关重要，其血液浓度维持在狭窄范围内。这是通过一个反馈回路实现的，该回路接收甲状旁腺细胞表面表达的钙敏感受体（CASR）的输入。响应低离子钙水平，甲状旁腺会增加甲状旁腺激素（PTH）的分泌，从而升高血清钙水平。CASR在肾脏中也高度表达，在那里它调节从原尿中重吸收钙。1型常染色体显性低钙血症（ADH）由CASR中的杂合激活突变引起，这些突变增加了CASR对细胞外离子钙的敏感性。因此，在正常离子钙浓度下，PTH的合成和分泌受到抑制。患者表现为低钙血症、高磷血症、低镁水平以及PTH水平低或低至正常。由于循环中PTH浓度降低以及肾小管CASR的激活，尿钙排泄通常会增加。目前正在研究使用CASR拮抗剂（钙敏感受体阻滞剂）治疗ADH的尝试。最近，在ADH患者中发现了G蛋白G11（Gα11）α亚基的杂合突变，这被归类为2型ADH。ADH2突变导致Gα11功能获得，Gα11是CASR信号传导的关键介质。因此，低钙血症的机制似乎与CASR激活突变相似，即甲状旁腺细胞对细胞外离子钙的敏感性增加。对CASR激活突变和Gα11功能获得性突变的研究有助于确定新的药物靶点，并改善1型和2型ADH患者的医疗管理。
