Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody

Makita, Noriko; Ando, Takao; Sato, Junichiro; Manaka, Katsunori; Mitani, Koji; Kikuchi, Yasuko; Niwa, Takashi; Ootaki, Masanori; Takeba, Yuko; Matsumoto, Naoki; Kawakami, Atsushi; Ogawa, Toshihisa; Nangaku, Masaomi; Iiri, Taroh

doi:10.1172/jci.insight.126449

Cited by 13 publications

(25 citation statements)

References 75 publications

(135 reference statements)

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“…Biased autoantibodies directed against the CaSR VFT can potentiate IP accumulation while inhibiting pERK1/2 generation (Makita et al, 2007;Makita and Iiri, 2014), whereas others inhibit pERK1/2 generation but have no effect on IP accumulation (Pallais et al, 2011). Importantly, cinacalcet corrected the severe hypercalcemia associated with acquired hypocalciuric hypercalcemia caused by a biased autoantibody (Makita et al, 2019). Taken together, these findings once again highlight how bias and allostery are key features of CaSR (patho)physiology and drug actions.…”

Section: Biased Agonism and Biased Allosteric Modulationmentioning

confidence: 73%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

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Section: Biased Agonism and Biased Allosteric Modulationmentioning

confidence: 73%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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“…Many genetic mutations that lead to loss or gain of function of the CaSR, have been identified in patients with metabolic syndromes (9,10). In addition, CaSR autoantibodies that modify the signaling properties of the receptor have been identified in rare diseases (11). Finally, CaSR is the target of three commercial drugs acting as a positive allosteric modulator (PAM).…”

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confidence: 99%

Illuminating the allosteric modulation of the calcium-sensing receptor

Liu

Zhao

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Many membrane receptors are regulated by nutrients. However, how these nutrients control a single receptor remains unknown, even in the case of the well-studied calcium-sensing receptor CaSR, which is regulated by multiple factors, including ions and amino acids. Here, we developed an innovative cell-free Förster resonance energy transfer (FRET)-based conformational CaSR biosensor to clarify the main conformational changes associated with activation. By allowing a perfect control of ambient nutrients, this assay revealed that Ca2+ alone fully stabilizes the active conformation, while amino acids behave as pure positive allosteric modulators. Based on the identification of Ca2+ activation sites, we propose a molecular basis for how these different ligands cooperate to control CaSR activation. Our results provide important information on CaSR function and improve our understanding of the effects of genetic mutations responsible for human diseases. They also provide insights into how a receptor can integrate signals from various nutrients to better adapt to the cell response.

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“…We also reported that this signal was mostly independent of Gi/o, the pertussis toxin (PTX)-sensitive G proteins, because treatment with PTX, which inhibits Gi/o signals, did not inhibit this signal (14,15). At a Ca level of 2.0 mM, IP1 accumulation was found to be augmented by the co-administration of each AHH patient's IgG at the time of Analysis-1 (Figure 3A), which was similar to the findings in the two previous cases we reported (14,15). After PSL treatment, Ca-stimulated IP accumulation decreased (Figure 3A) in Pt-1 (Figure 1A, Analysis-2).…”

Section: Effects Of Ahh Patient Igg On Ca-stimulated Ip1 Accumulation...mentioning

confidence: 99%

“…As an acquired disease analogous to ADH1, acquired hypoparathyroidism, including immune-checkpoint inhibitor-related hypoparathyroidism, has been reported to be caused by activating autoantibodies against CaSR (29)(30)(31)(32)(33)(34). Acquired hypocalciuric hypercalcemia (AHH), which is analogous to FHH1 or NSHPT, has been reported to be caused also by autoantibodies against CaSR (14,15,(35)(36)(37)(38). Depending on the reported AHH cases, autoantibodies work either as pure blocking entities (35) or in a biased manner (14,15).…”

Section: Introductionmentioning

confidence: 99%

“…Acquired hypocalciuric hypercalcemia (AHH), which is analogous to FHH1 or NSHPT, has been reported to be caused also by autoantibodies against CaSR (14,15,(35)(36)(37)(38). Depending on the reported AHH cases, autoantibodies work either as pure blocking entities (35) or in a biased manner (14,15). By investigating their mode of action, both the pathophysiological mechanisms underlying this heterologous disease from the perspective of the epitopes detected and possible effective treatments, and the physiological mechanisms by which PTH secretion is regulated in the human body, have been further elucidated (15).…”

Section: Introductionmentioning

confidence: 99%

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

Makita¹,

Sato²,

Manaka³

et al. 2022

JCI Insight

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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.

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Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody

Cited by 13 publications

References 75 publications

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Illuminating the allosteric modulation of the calcium-sensing receptor

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

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