Allosteric modulators of the human calcium-sensing receptor: structures, sites of action, and therapeutic potentials.
The human extracellular Ca(2+)-sensing receptor (CaR) plays a key role in the regulation of serum calcium and parathyroid hormone. This large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites. Positive allosteric modulators of the CaR, which increase CaR activation and thereby decrease secretion of parathyroid hormone, are potential for the treatment of primary and secondary hyperparathyroidism. Conversely, negative allosteric modulators of the CaR, which decrease the receptor activation and thereby stimulate endogenous parathyroid hormone secretion, are potential for the treatment of osteoporosis and autosomal dominant hypocalcemia. Significant progress has been made in recent years in screening for allosteric modulators selectively targeting the CaR and identification of receptor residues important for allosteric modulation.
Hu
Jianxin
J
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA. jianxinh@niddk.nih.gov
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D044169:Receptors, Calcium-Sensing / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology
D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled