Successful prednisolone or calcimimetic treatment of acquired hypocalciuric hypercalcemia caused by biased allosteric CaSR autoantibodies

Abstract

Biased agonism is a frontier field in G-protein coupled receptor (GPCR) research.Acquired hypocalciuric hypercalcemia (AHH) is a rare disease caused by calciumsensing receptor (CaSR) autoantibodies, to date, showing either simple blocking or biased properties (i.e., stimulatory or blocking effects on different downstream signaling pathways). This emphasizes the importance of the Gi/o (pertussis toxin-sensitive G proteins, whose  subunits activate multiple signals including ERK1/2) in regulating PTH secretion. We here describe three patients with symptomatic AHH that shared characteristics with the two cases we previously reported as follows: [1] aged (between 74-87 years at diagnosis); [2] male; [3] unexpectedly showed no other autoimmune diseases; [4] showed spontaneously fluctuating calcium levels from approximately normal to near fatally high ranges; [5] acute exacerbations could be successfully treated with prednisolone and/or calcimimetics; [6] the presence of CaSR autoantibodies that operated as biased allosteric modulators of CaSR; and that [7] were likely to be conformational (i.e., recognizing and thereby stabilizing a unique active conformation of CaSR that activates Gq/11, activating phosphatidylinositol turnover, but not Gi/o). Our observations with these prominent commonalities may provide new insights into the phenotype and characteristics of AHH and the mechanisms by which the biased agonism 4 of GPCRs operate.