Pharmacological Chaperones: Potential for the Treatment of Hereditary Diseases Caused by Mutations in G Protein‐Coupled Receptors

Valenzano, Kenneth J.; Elias, Benjamin; René, Patricia; Bouvier, Michel

doi:10.1002/9780470627327.ch17

Cited by 4 publications

(6 citation statements)

References 279 publications

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“…In many GPCR disease-causing mutations, forward trafficking of receptors is impeded as a result of their misfolding and sequestration in the endoplasmic reticulum (ER) 6 7 . Examples include the V2R and melanocortin type 4 receptor (MC4R) involved in nephrogenic diabetes insipidus and early-onset obesity, respectively 38 39 .…”

Section: Resultsmentioning

confidence: 99%

“…Recent findings suggest that receptor trafficking can be differentially regulated by ligands 3 4 , potentially affecting cell responsiveness and drug efficacies. Moreover, for naturally occurring mutations in GPCRs that poorly traffic to the PM, the use of pharmacological chaperones (PCs) can rescue receptor functions at the PM and ensuing cellular responses 5 6 7 . Advantages can thus be obtained, both in drug and basic research discovery programs, from developing means to efficiently study receptor trafficking.…”

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confidence: 99%

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Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET

et al. 2016

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Endocytosis and intracellular trafficking of receptors are pivotal to maintain physiological functions and drug action; however, robust quantitative approaches are lacking to study such processes in live cells. Here we present new bioluminescence resonance energy transfer (BRET) sensors to quantitatively monitor G protein-coupled receptors (GPCRs) and β-arrestin trafficking. These sensors are based on bystander BRET and use the naturally interacting chromophores luciferase (RLuc) and green fluorescent protein (rGFP) from Renilla. The versatility and robustness of this approach are exemplified by anchoring rGFP at the plasma membrane or in endosomes to generate high dynamic spectrometric BRET signals on ligand-promoted recruitment or sequestration of RLuc-tagged proteins to, or from, specific cell compartments, as well as sensitive subcellular BRET imaging for protein translocation visualization. These sensors are scalable to high-throughput formats and allow quantitative pharmacological studies of GPCR trafficking in real time, in live cells, revealing ligand-dependent biased trafficking of receptor/β-arrestin complexes.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET

et al. 2016

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“…71,72 In most cases, the mechanism of retention was attributed to receptor mutations. Based on our study in mice, a pathological deregulation of gatekeeper content could represent an additional mechanism in this context.…”

Section: Discussionmentioning

confidence: 98%

GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper

et al. 2015

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Endoplasmic reticulum (ER) release and cell-surface export of many G protein-coupled receptors (GPCRs) are tightly regulated. For gamma-aminobutyric acid (GABA)B receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell-surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gatekeepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function.

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“…Type II mutants have defective intracellular transport, so that they cannot reach the cell surface and are trapped in the interior of the cell. 153 Other membrane-permeable GPCR antagonists that do not bind to V2R, did not rescue cell surface expression of the NDI V2R mutants, corroborating that the compounds need to bind to the mutant receptor to promote its release from the ER. It was determined that the vast majority of the mutations causing NDI are type II or trafficking mutations.…”

Section: Arginine Vasopressin Receptor 2 (Avpr2 or V2r)mentioning

confidence: 96%

Small Molecules That Target Protein Misfolding

2012

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Protein misfolding is a process in which proteins are unable to attain or maintain their biologically active conformation. Factors contributing to protein misfolding include missense mutations and intracellular factors such as pH changes, oxidative stress, or metal ions. Protein misfolding is linked to a large number of diseases such as cystic fibrosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and less familiar diseases such as Gaucher's disease, nephrogenic diabetes insipidus, and Creutzfeldt-Jakob disease. In this Perspective, we report on small molecules that bind to and stabilize the aberrant protein, thereby helping it to attain a native or near-native conformation and restoring its function. The following targets will be specifically discussed: transthyretin, p53, superoxide dismutase 1, lysozyme, serum amyloid A, prions, vasopressin receptor 2, and α-1-antitrypsin.

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Pharmacological Chaperones: Potential for the Treatment of Hereditary Diseases Caused by Mutations in G Protein‐Coupled Receptors

Cited by 4 publications

References 279 publications

Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET

Monitoring G protein-coupled receptor and β-arrestin trafficking in live cells using enhanced bystander BRET

GABAB receptor cell-surface export is controlled by an endoplasmic reticulum gatekeeper

Small Molecules That Target Protein Misfolding

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