G-protein coupled receptors (GPCRs) comprise the largest superfamily within the human proteome, and are frequent targets for hormones and drugs. Important insights about the roles of GPCRs in endocrinology have been provided by studies of clinical disorders, as illustrated by those of calcium regulation, which involves the parathyroids, first discovered in an Indian Rhinoceros by Sir Richard Owen in 1849. The parathyroids and kidneys express the extracellular calcium-sensing receptor (CaSR), a family C GPCR, that regulates calcium homeostasis by detecting alterations in plasma calcium concentrations and activating G-protein mediated signalling cascades, which modulate parathyroid hormone secretion and urinary calcium excretion. The gene encoding the CaSR is located on chromosome 3q21.1, and CaSR mutations resulting in loss-of-function or gain-of-function lead to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalcaemia (ADH), respectively. Such CaSR mutations are detected in ~65% of FHH patients, referred to as FHH type 1 (FHH1), and ~70% of ADH patients, referred to as ADH1. Genetic linkage studies in other FHH kindreds had revealed additional loci on chromosomes 19p and 19q13.3, designated FHH2 and FHH3, respectively, indicating genetic heterogeneity for FHH. A hypothesis-driven study established that FHH2 and ADH2 are due to loss-of-function and gain-of-function mutations of G-protein subunit α11 (Gα11), encoded by GNA11. A hypothesis-generating study established that FHH3 is due to loss-of function mutations affecting adaptor protein-2 sigma subunit (AP2σ). AP2, a hetrotetrameric complex, is involved in clathrin-mediated endocytosis and FHH3-associated AP2σ mutations, which all affect the Arg15 residue that interacts with the dileucine motif of cargo proteins and comprise Arg15Cys, Arg15His and Arg15Leu, result in increased CaSR cell surface expression likely due to decreased CaSR internalisation. Such AP2σ mutations are found in >20% of FHH patients who do not have CaSR or Gα11 mutations. These studies have provided new insights into GPCR signalling and trafficking.