Citation Information: JCI Insight. 2022;7(20):e156742. https://doi.org/10.1172/jci.insight.156742.
Abstract
Biased agonism is a frontier field in GPCR research. Acquired hypocalciuric hypercalcemia (AHH) is a rare disease caused by calcium-sensing 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 βγ subunits activate multiple signals, including ERK1/2) in regulating parathyroid hormone secretion. We here describe 3 patients with symptomatic AHH who shared characteristics with the 2 cases we previously reported as follows: (a) elderly (74–87 years at diagnosis), (b) male, (c) unexpectedly showed no other autoimmune diseases, (d) showed spontaneously fluctuating Ca levels from approximately normal to near fatally high ranges, (e) acute exacerbations could be successfully treated with prednisolone and/or calcimimetics, (f) the presence of CaSR autoantibodies that operated as biased allosteric modulators of CaSR, and (g) 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 of GPCRs operate.
Authors
Noriko Makita, Junichiro Sato, Katsunori Manaka, Kimiko Akahane, Takahiro Ito, Hajime Yamazaki, Akira Mizoguchi, Yusuke Hikima, Hirofumi Horikoshi, Masaomi Nangaku, Taroh Iiri
Figure 5
Ca-dependent pERK and the effects of PTX and YM in HEK293 cells stably expressing CaSR.
