Inherited endocrine diseases involving G proteins and G protein-coupled receptors

Naturally occurring mutations in the G protein Gs-α subunit and in a number of G protein-coupled receptors (GPCRs) have been identified in human diseases. Loss-offunction mutations in GPCRs for various hormones lead to hormone resistance manifest as hypofunction of the gland expressing the affected GPCR. Conversely, GPCR gain-offunction mutations lead to hormone-independent activation and hyperfunction of the involved gland. Our laboratory has focused on the extracellular calcium-sensing GPCR (CaR) expressed primarily, but not exclusively, in parathyroid glands and kidney. Loss-offunction CaR mutations lead to a form of hyperparathyroidism, an apparent exception to the general pattern described above, but in fact reflecting resistance to the normal inhibition of parathyroid hormone secretion by the 'hormone' agonist, extracellular Ca²⁺. CaR gain-of function-mutations cause autosomal dominant hypocalcemia due to activation of the receptor at subphysiologic concentrations of serum Ca2²⁺, leading to 'inappropriate' inhibition of parathyroid hormone secretion. I will describe our recent work that helps inform design of novel therapeutics targeting this important GPCR.