Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia
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- Makita Noriko
- Department of Endocrinology and Nephrology, The University of Tokyo School of Medicine, Tokyo 113-8655 Japan
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- Iiri Taroh
- Department of Endocrinology and Nephrology, The University of Tokyo School of Medicine, Tokyo 113-8655 Japan
書誌事項
- タイトル別名
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- Biased agonism: a novel paradigm in G protein-coupled receptor signaling observed in acquired hypocalciuric hypercalcemia [Review]
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抄録
The classical model of G protein-coupled receptor (GPCR) activation is the two-state model, in which the GPCR exists in equilibrium between an active and inactive state. Based on this model, GPCR ligands have been classified as agonists, inverse agonists, or antagonists depending on their actions in shifting this equilibrium. Recently, however, accumulating evidence has indicated that GPCRs may exist in multiple active and inactive conformational states. In this situation, each ligand recognizes and stabilizes a specific conformation of the GPCR, leading to a set of specific biological effects. Based on this new model, a unique agonist or a combination of the usual agonist and an allosteric modulator may enable activation of a specific signaling pathway via a GPCR that activates multiple signals (biased agonism, functional selectivity). The calcium-sensing receptor autoantibody that we have identified in the serum of a patient with acquired hypocalciuric hypercalcemia (AHH) is the first example of a biased allosteric modulator of a GPCR working in a pathophysiological context. Our findings may indicate the presence of physiological allosteric modulators and provide new directions for the future drug development.
収録刊行物
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- Endocrine Journal
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Endocrine Journal 61 (4), 303-309, 2014
一般社団法人 日本内分泌学会