Pharmacoperone rescue of vasopressin 2 receptor mutants reveals unexpected constitutive activity and coupling bias

Spicer, Timothy; Bannister, Thomas D.; Scampavia, Louis; Conn, P. Michael

doi:10.1371/journal.pone.0181830

Cited by 13 publications

(3 citation statements)

References 63 publications

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“…Since they are trapped in the ER, their presence on the plasma membrane are reduced and consequently their agonist sensitivity were reduced. Some of the intracellularly trapped mutants can be rescued using with PCs and it is shown that AVPR2 mutants could be rescued by this strategy [14,[20][21][22]. With the help of PCs, which are cell-permeable small molecules, mutant receptors can fold properly and pass the ER quality control system.…”

Section: Discussionmentioning

confidence: 99%

The rescue potentials of OPC-41061, OPC-31260 and OPC-21268 on mutant AVPR2s that cause nephrogenic diabetes insipidus

Şahin

Tuncdemir

Ozer

et al. 2023

Preprint

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Purpose Nephrogenic Diabetes insipidus (NDI) is a rare disease which is characterized by polyuria and polydipsia. AVPR2 mutations can cause NDI. Mutants may not function properly since the mutations can affect their folding process and make them be trapped in the Endoplasmic reticulum (ER). Recent studies showed that pharmacological chaperones (PCs) may rescue mutant AVPR2s and they can be functional again. OPC-41061, OPC-31260 and OPC-21268 are these kind of PCs and they can specifically bind to the mutant AVPR2s and rescue them from ER via helping their folding process. In this study, the effects of OPC-41061, OPC-31260 and OPC-21268 on AVPR2 mutants (R68W, ΔR67-G69/G107W, V162A and T273M) were analyzed. Methods We performed cell surface and total ELISA, and cAMP accumulation assay for mutant AVPR2s after the treatment with 3 different PCs. Results It was observed that OPC-41061 improved cell surface expressions of all mutants except V162A and ΔR67-G69/G107W, and cell surface expressions of R68W and ΔR67-G69 were increased with all three PCs. Then mutants were stimulated with their agonists to measure cAMP accumulation in the cell as a functional analysis. As a result, we found that R68W and ΔR67-G69 (except T273M) were rescued and could be functional after the treatment with OPC-41061 and OPC-31260. Conclusion Showing specific rescue potential of these kind of PCs has an importance on the development of new treatment strategies on NDI. Determining the responses of mutant proteins to various chaperones is extremely important for current treatment approaches and identifying the new PCs.

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Section: Discussionmentioning

confidence: 99%

The rescue potentials of OPC-41061, OPC-31260 and OPC-21268 on mutant AVPR2s that cause nephrogenic diabetes insipidus

Şahin

Tuncdemir

Ozer

et al. 2023

Preprint

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“…Currently, these methods mainly involve the following mechanisms: (1) AVPR2 antagonists and cell-permeable AVPR2 antagonists act as molecular chaperones and are mainly administered to patients with AVPR2 missense mutations[ 19 ]. Targeting chemical and molecular chaperones appropriately corrects the point mutations that cause misfolded disease-causing proteins, rescuing mutant proteins from ER retention and allowing correctly folded proteins to be delivered in cells[ 19 , 20 ]; (2) AVPR2 agonists, some of which are cell permeability agonists, can bind AVPR2 mutants trapped in the ER, but they do not stabilize their conformation and can directly activate AVPR2 mutants within these cells by signaling to transmit a preformed receptor-G protein-adenylate cyclase complex. The subsequent generation of cAMP activates PKA, resulting in AQP2 phosphorylation and plasma membrane expression, thereby attenuating the NDI phenotype[ 4 , 19 ]; (3) Some classic treatment modalities, including vasopressin analogs, prostaglandin receptor agonists, hormone receptor agonists, and cGMP phosphodiesterase inhibitors, can bypass the defective AVPR2 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Congenital nephrogenic diabetes insipidus arginine vasopressin receptor 2 gene mutation at new site: A case report

Xu¹,

Jianli²,

Zhao³

et al. 2022

World J Clin Cases

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BACKGROUND Congenital nephrogenic diabetes insipidus (CNDI) is a rare hereditary disorder. It is associated with mutations in the arginine vasopressin receptor 2 (AVPR2) gene and aquaporin 2 (AQP2) gene, and approximately 270 different mutation sites have been reported for AVPR2. Therefore, new mutations and new manifestations are crucial to complement the clinical deficiencies in the diagnosis of this disease. We report a case of a novel AVPR2 gene mutation locus and a new clinical mani-festation. CASE SUMMARY We describe the case of a 48-d-old boy who presented with recurrent fever and diarrhea 5 d after birth. Laboratory tests showed electrolyte disturbances and low urine specific gravity, and imaging tests showed no abnormalities. Genetic testing revealed a novel X-linked recessive missense mutation, c.283 (exon 2) C>T (p.P95S). This mutation results in the substitution of a proline residue with a serine residue in the AVPR2 protein sequence. The diagnosis of CNDI was confirmed based on the AVPR2 gene mutation. The treatment strategy for this patient was divided into two stages, including physical cooling supplemented with appropriate amounts of water in the early stage and oral hydrochlorothia-zide (1-2 mg/kg) after a clear diagnosis. After follow-up of one and a half years, the patient gradually improved. CONCLUSION AVPR2 gene mutations in new loci and new clinical symptoms help clinicians understand this disease and shorten the diagnosis cycle.

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“…Importantly, biased responses can be elicited by biased ligands, biased receptors, or system bias, all of which can lead to preferential signaling through G proteins or β-arrestins ( Smith et al, 2018 ). Biased agonism has been studied at several GPCRs, including G q/11 -coupled receptors ( Sanchez-Fernandez et al, 2013 ; Cabana et al, 2015 ; Mancini et al, 2015 ; Janovick et al, 2017 ; Teixeira et al, 2017 ). However, TRH-R has not received much attention in this regard.…”

Section: Thyrotropin-releasing Hormone Receptor-mediated Signalingmentioning

confidence: 99%

Biochemical and physiological insights into TRH receptor-mediated signaling

Trubacova

Drastichova

Novotný

2022

Front. Cell Dev. Biol.

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Thyrotropin-releasing hormone (TRH) is an important endocrine agent that regulates the function of cells in the anterior pituitary and the central and peripheral nervous systems. By controlling the synthesis and release of thyroid hormones, TRH affects many physiological functions, including energy homeostasis. This hormone exerts its effects through G protein-coupled TRH receptors, which signal primarily through Gq/11 but may also utilize other G protein classes under certain conditions. Because of the potential therapeutic benefit, considerable attention has been devoted to the synthesis of new TRH analogs that may have some advantageous properties compared with TRH. In this context, it may be interesting to consider the phenomenon of biased agonism and signaling at the TRH receptor. This possibility is supported by some recent findings. Although knowledge about the mechanisms of TRH receptor-mediated signaling has increased steadily over the past decades, there are still many unanswered questions, particularly about the molecular details of post-receptor signaling. In this review, we summarize what has been learned to date about TRH receptor-mediated signaling, including some previously undiscussed information, and point to future directions in TRH research that may offer new insights into the molecular mechanisms of TRH receptor-triggered actions and possible ways to modulate TRH receptor-mediated signaling.

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Pharmacoperone rescue of vasopressin 2 receptor mutants reveals unexpected constitutive activity and coupling bias

Cited by 13 publications

References 63 publications

The rescue potentials of OPC-41061, OPC-31260 and OPC-21268 on mutant AVPR2s that cause nephrogenic diabetes insipidus

The rescue potentials of OPC-41061, OPC-31260 and OPC-21268 on mutant AVPR2s that cause nephrogenic diabetes insipidus

Congenital nephrogenic diabetes insipidus arginine vasopressin receptor 2 gene mutation at new site: A case report

Biochemical and physiological insights into TRH receptor-mediated signaling

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