Mutations in G proteins and G protein-coupled receptors in human endocrine diseases

Summary

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. Such mutations may lead to loss or gain of function of the encoded protein. Study of such naturally occurring, disease-causing mutations offers unique insights into G protein and GPCR structure and function. In general, diseases caused by GPCR loss-of-function mutations are inherited in autosomal recessive fashion, and those caused by gain-of-function mutations are inherited in autosomal dominant fashion. Endocrine gland dysfunction is the most frequently recognized consequence of GPCR mutation. Loss-of- function mutations in GPCRs for various hormones lead to hormone resistance, manifested as hypofunction of the gland expressing the affected GPCR. Conversely, GPCR gain-of-function mutations lead to hormone-independent activation and hyperfunction of the involved gland.

In recent years, our lab has focused on the extracellular calcium-sensing GPCR (CaR) expressed primarily, but not exclusively, in parathyroid glands and kidney. Loss-of-function 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 (PTH) secretion by the “hormone” agonist, extracellular Ca⁺⁺. CaR gain-of-function mutations cause autosomal dominant hypocalcemia (ADH), due to activation of the receptor at subphysiologic concentrations of serum Ca⁺⁺, leading to “inappropriate” inhibition of PTH secretion. Mutations identified in subjects with ADH are missense mutations clustered in discrete regions of the large extracellular domain (ECD) or seven-transmembrane (7TM) domain of this family 3 GPCR. Expression studies of such mutations have allowed us to identify regions in the ECD and 7TM domains that are critical for activation of the receptor by Ca⁺⁺ and by allosteric modulators of the receptor. I will describe our recent work that helps inform the design of novel therapeutics targeting this important GPCR.