Hauache O M
Laboratório de Endocrinologia Molecular, Disciplina de Endocrinologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil.
Braz J Med Biol Res. 2001 May;34(5):577-84. doi: 10.1590/s0100-879x2001000500004.
The recently cloned extracellular calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays an essential role in the regulation of extracellular calcium homeostasis. This receptor is expressed in all tissues related to this control (parathyroid glands, thyroid C-cells, kidneys, intestine and bones) and also in tissues with apparently no role in the maintenance of extracellular calcium levels, such as brain, skin and pancreas. The CaR amino acid sequence is compatible with three major domains: a long and hydrophilic aminoterminal extracellular domain, where most of the activating and inactivating mutations described to date are located and where the dimerization process occurs, and the agonist-binding site is located, a hydrophobic transmembrane domain involved in the signal transduction mechanism from the extracellular domain to its respective G protein, and a carboxyterminal intracellular tail, with a well-established role for cell surface CaR expression and for signal transduction. CaR cloning was immediately followed by the association of genetic human diseases with inactivating and activating CaR mutations: familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism are caused by CaR-inactivating mutations, whereas autosomal dominant hypoparathyroidism is secondary to CaR-activating mutations. Finally, we will comment on the development of drugs that modulate CaR function by either activating (calcimimetic drugs) or antagonizing it (calcilytic drugs), and on their potential therapeutic implications, such as medical control of specific cases of primary and uremic hyperparathyroidism with calcimimetic drugs and a potential treatment for osteoporosis with a calcilytic drug.
最近克隆出的细胞外钙敏感受体（CaR）是一种G蛋白偶联受体，在细胞外钙稳态调节中起关键作用。该受体在所有与这种调节相关的组织（甲状旁腺、甲状腺C细胞、肾脏、肠道和骨骼）中表达，也在一些明显与细胞外钙水平维持无关的组织中表达，如脑、皮肤和胰腺。CaR的氨基酸序列与三个主要结构域相符：一个长的亲水性氨基末端细胞外结构域，迄今描述的大多数激活和失活突变都位于此，二聚化过程也在此发生，激动剂结合位点也位于此；一个参与从细胞外结构域到其各自G蛋白的信号转导机制的疏水性跨膜结构域；以及一个羧基末端细胞内尾巴，在细胞表面CaR表达和信号转导中具有明确作用。CaR克隆后紧接着就发现了人类遗传疾病与CaR失活和激活突变的关联：家族性低钙血症性高钙血症和新生儿重症甲状旁腺功能亢进是由CaR失活突变引起的，而常染色体显性遗传性甲状旁腺功能减退继发于CaR激活突变。最后，我们将评论通过激活（拟钙剂药物）或拮抗（钙解剂药物）来调节CaR功能的药物的研发情况，以及它们潜在的治疗意义，比如用拟钙剂药物对原发性和尿毒症性甲状旁腺功能亢进的特定病例进行医学控制，以及用钙解剂药物对骨质疏松症进行潜在治疗。
