Brown E M, Chattopadhyay N, Vassilev P M, Hebert S C
Department of Medicine, Brigham and Women's Hospital, Boston, Massachussetts 02115, USA.
Recent Prog Horm Res. 1998;53:257-80; discussion 280-1.
The ability of parathyroid cells to recognize and respond to (i.e., "sense") small changes in the extracellular Ca2+ concentration (Ca2+o) plays a crucial role in mineral ion homeostasis. Expression cloning in Xenopus laevis oocytes enabled isolation of a cDNA coding for the bovine parathyroid CaR. CaRs were later isolated from human parathyroid and kidney, rat kidney, brain and C-cell, rabbit kidney, and chicken parathyroid. All are tissue and species homologs of the same ancestral gene. The predicted CaR protein has a large extracellular amino-terminus, which binds polycationic CaR agonists; a central core with seven membrane-spanning helices, documenting that it is a G protein-coupled receptor; and an approximately 200 amino acid carboxyl-terminal tail. The CaR is highly expressed in parathyroid and C-cells, along almost the entire nephron and gastrointestinal (GI) tract and within numerous regions of the brain, particularly hippocampus, cerebellum, and hypothalamus. The CaR's physiological importance has been documented by the identification of hyper- and hypocalcemic syndromes due to inactivating or activating CaR mutations, respectively. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are caused by loss-of-function CaR mutations producing Ca2+o "resistance," while autosomal dominant hypocalcemia is the result of activating mutations rendering CaRs overly sensitive to Ca2+o. In addition to showing altered parathyroid responsiveness to Ca2+o, patients with FHH reabsorb too much urinary Ca2+ and Mg2+ at a given Ca2+o, while those with autosomal dominant hypocalcemia excrete too much, illustrating the CaR's key role in renal handling of divalent cations. Recent in vitro data suggest that the CaR directly regulates renal water handling in the collecting duct. Indeed, patients with FHH concentrate their urine normally, despite their hypercalcemia, while those with autosomal dominant hypocalcemia can exhibit impaired urinary concentration at normal or even low Ca2+o, suggesting that the CaR enables coordination of renal calcium and water handling. In addition to serving these "homeostatic" roles, the CaR likely also enables Ca2+o to serve additional roles as an extracellular messenger. The receptor regulates key Ca2+ and K(+)-permeable ion channels in hippocampal and other brain cells and likely senses local changes in Ca2+o within the brain microenvironment accompanying neuronal activation. It is also present in and regulates ion channels in lens epithelial cells, potentially playing some role in cataract development in hypoparathyroid patients. In keratinocytes and epithelial cells of the gastrointestinal tract, in contrast, the CaR may regulate cellular proliferation and differentiation, processes known to be modulated by Ca2+o in these cell types. Thus, in addition to sensing and regulating systemic Ca2+o, the CaR likely enables Ca2+o to act as a local signal for cells within specific microenvironments, such as the brain or eye.
甲状旁腺细胞识别并响应（即“感知”）细胞外Ca2+浓度（Ca2+o）的微小变化的能力在矿物质离子稳态中起着至关重要的作用。在非洲爪蟾卵母细胞中进行的表达克隆使得能够分离出编码牛甲状旁腺钙敏感受体（CaR）的cDNA。随后从人甲状旁腺和肾脏、大鼠肾脏、大脑和C细胞、兔肾脏以及鸡甲状旁腺中分离出了CaR。所有这些都是同一祖先基因的组织和物种同源物。预测的CaR蛋白有一个大的细胞外氨基末端，可结合多阳离子CaR激动剂；一个具有七个跨膜螺旋的中央核心，证明它是一种G蛋白偶联受体；以及一个约200个氨基酸的羧基末端尾巴。CaR在甲状旁腺和C细胞中高度表达，沿几乎整个肾单位和胃肠道以及大脑的许多区域，特别是海马体、小脑和下丘脑。通过分别鉴定由于CaR失活或激活突变导致的高钙血症和低钙血症综合征，证明了CaR的生理重要性。家族性低钙血症性高钙血症（FHH）和新生儿重症甲状旁腺功能亢进症（NSHPT）是由功能丧失的CaR突变导致Ca2+o“抵抗”引起的，而常染色体显性低钙血症是激活突变使CaR对Ca2+o过度敏感的结果。除了甲状旁腺对Ca2+o的反应性改变外，FHH患者在给定的Ca2+o水平下重吸收过多的尿Ca2+和Mg2+，而常染色体显性低钙血症患者排泄过多，这说明了CaR在肾脏处理二价阳离子中的关键作用。最近的体外数据表明，CaR直接调节集合管中的肾脏水代谢。事实上，FHH患者尽管有高钙血症，但尿液浓缩正常，而常染色体显性低钙血症患者在正常甚至低Ca2+o水平下可能表现出尿液浓缩受损，这表明CaR能够协调肾脏钙和水的代谢。除了发挥这些“稳态”作用外，CaR可能还使Ca2+o能够作为细胞外信使发挥其他作用。该受体调节海马体和其他脑细胞中的关键Ca2+和K(+)通透性离子通道，并可能感知伴随神经元激活的大脑微环境中Ca2+o的局部变化。它也存在于晶状体上皮细胞中并调节离子通道，可能在甲状旁腺功能减退患者的白内障形成中起一定作用。相比之下，在角质形成细胞和胃肠道上皮细胞中，CaR可能调节细胞增殖和分化，这些过程已知在这些细胞类型中受Ca2+o调节。因此，除了感知和调节全身Ca2+o外，CaR可能还使Ca2+o能够作为特定微环境（如大脑或眼睛）中细胞的局部信号。
