The calcium-sensing receptor (CaSR) is a pleiotropic G protein-coupled receptor that couples to multiple G proteins, including Gq/11 and Gi/o, to maintain extracellular calcium homeostasis. Acquired hypocalciuric hypercalcemia (AHH) is a rare disorder caused by autoantibodies against the CaSR. Although initially assumed to simply block receptor function, we identified CaSR autoantibodies with unexpected signaling properties.
The autoantibodies enhanced CaSR-mediated phosphatidylinositol turnover while attenuating pertussis toxin-sensitive ERK phosphorylation, leading us to propose that they act as biased allosteric modulators preferentially activating Gq/11 over Gi/o signaling. However, this interpretation was initially based on downstream signaling readouts, with ERK phosphorylation serving as a surrogate for Gi/o activation. More recently, direct assessment of G-protein activation has demonstrated enhanced Gq/11 and impaired Gi/o coupling, providing direct evidence for antibody-induced signaling bias.
These findings raise a physiological paradox: how can an antibody that enhances Gq/11 signaling produce a phenotype resembling loss of CaSR function? The critical role of Gq/11 signaling in CaSR-mediated regulation of PTH secretion is well supported by genetic evidence from human disease and experimental models. Our studies using human parathyroid cells, however, indicate that Gi/o signaling also contributes importantly to PTH suppression. Thus, physiological CaSR output may reflect integration of Gq/11 and Gi/o signaling rather than Gq/11 activity alone.
We have now identified an expanding series of patients with AHH whose autoantibodies exhibit remarkably similar functional properties and who share a common HLA background, suggesting that AHH may represent a distinct HLA-associated autoimmune disease.
Together, these observations reveal new dimensions of CaSR biology, linking G-protein signaling bias and physiological signal integration to receptor-directed autoimmunity.