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Extracellular calcium-sensing receptor: structural and functional features and association with diseases
1Laboratório de Endocrinologia Molecular, Disciplina de Endocrinologia, Departamento de Medicina, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brasil. endo@pesquisa.emp.br
Abstract:
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.
Insights
The calcium-sensing receptor (CaR) regulates calcium levels. Mutations in CaR cause genetic disorders, and drugs targeting CaR show therapeutic potential for hyperparathyroidism and osteoporosis.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- The extracellular calcium-sensing receptor (CaR) is a G protein-coupled receptor crucial for calcium homeostasis.
- CaR is expressed in various tissues, including parathyroid glands, kidneys, and brain.
- The CaR protein comprises extracellular, transmembrane, and intracellular domains, each with specific functions.
Purpose of the Study:
- To review the structure and function of the calcium-sensing receptor (CaR).
- To discuss the association of CaR mutations with human genetic diseases.
- To explore the therapeutic potential of CaR-modulating drugs.
Main Methods:
- Review of existing literature on CaR cloning, genetics, and pharmacology.
- Analysis of CaR structure-function relationships.
- Discussion of clinical implications of CaR research.
Main Results:
- CaR mutations are linked to familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypoparathyroidism.
- Activating CaR mutations cause hypoparathyroidism, while inactivating mutations lead to hypercalcemia disorders.
- Calcimimetic and calcilytic drugs are being developed to modulate CaR activity.
Conclusions:
- CaR plays a vital role in calcium regulation and is implicated in several genetic disorders.
- Targeting CaR with drugs offers promising therapeutic strategies for conditions like hyperparathyroidism and osteoporosis.