Analysis of the V2 Vasopressin Receptor (V2R) Mutations Causing Partial Nephrogenic Diabetes Insipidus Highlights a Sustainable Signaling by a Non-peptide V2R Agonist.
Disease-causing mutations in G protein-coupled receptor (GPCR) genes, including the V2 vasopressin receptor (V2R) gene, often cause misfolded receptors, leading to a defect in plasma membrane trafficking. A novel V2R mutation, T273M, identified in a boy with partial nephrogenic diabetes insipidus (NDI), shows intracellular localization and partial defects similar to the two mutants we described previously (10). Although non-peptide V2R antagonists have been shown to rescue the membrane localization of V2R mutants, their level of functional rescue is weak. Interestingly, it has been reported that a non-peptide agonist, OPC51803, activates misfolded V2R mutants intracellularly without degradation, thus potentially serving as a therapeutic agent against NDI (14). In our current experiments, however, a peptide antagonist blocked arginine vasopressin (AVP)- or OPC51803-stimulated cAMP accumulation both in COS-7 and MDCK cells, suggesting that OPC51803 mainly stimulates cell surface V2R mutants. In addition, our analyses revealed that OPC51803 works not only as a non-peptide agonist that causes activation/β-arrestin-dependent desensitization of V2R mutants expressed at the plasma membrane but also as a pharmacochaperone that promotes the endoplasmic reticulum-retained mutant maturation and trafficking to the plasma membrane. The ratio of the pharmacochaperone effect to the desensitization effect likely correlates negatively with the residual function of the tested mutants, suggesting that OPC5 has a more favorable effect on the V2R mutants with a less residual function. We speculated that the canceling of the desensitization effect of OPC51803 by the pharmacochaperone effect after long-term treatment may produce sustainable signaling, and thus pharmacochaperone agonists such as OPC51803 may serve as promising therapeutics for NDI caused by misfolded V2R mutants.
From the Department of Endocrinology and Nephrology, University of Tokyo, Tokyo 113-8655, Japan, norimaki-tky@umin.ac.jp.
Noriko
N
Makita
the Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, 036-8562 Japan, and.
Tomohiko
T
Sato
From the Department of Endocrinology and Nephrology, University of Tokyo, Tokyo 113-8655, Japan.
Yuki
Y
Yajima-Shoji
From the Department of Endocrinology and Nephrology, University of Tokyo, Tokyo 113-8655, Japan.
Junichiro
J
Sato
From the Department of Endocrinology and Nephrology, University of Tokyo, Tokyo 113-8655, Japan.
Katsunori
K
Manaka
From the Department of Endocrinology and Nephrology, University of Tokyo, Tokyo 113-8655, Japan.
Makiko
M
Eda-Hashimoto
the Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
Masanori
M
Ootaki
the Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
Naoki
N
Matsumoto
From the Department of Endocrinology and Nephrology, University of Tokyo, Tokyo 113-8655, Japan.
Masaomi
M
Nangaku
From the Department of Endocrinology and Nephrology, University of Tokyo, Tokyo 113-8655, Japan, tiiri-tky@umin.ac.jp.|the Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan.
Taroh
T
Iiri
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D018500:Diabetes Insipidus, Nephrogenic / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009154:Mutation; D011759:Pyrrolidines / Q000494:pharmacology*; D017483:Receptors, Vasopressin / Q000819:agonists / Q000235:genetics / Q000378:metabolism
D001552:Benzazepines; C409942:OPC 51803; D011759:Pyrrolidines; D017483:Receptors, Vasopressin
G protein-coupled receptor (GPCR); membrane trafficking; molecular chaperone; receptor regulation; signal transduction