Genetic Vulnerability of GPCRs: A Call to Action

doi:10.1016/j.tibs.2018.02.006

Trends in Biochemical Sciences

Volume 43, Issue 4, April 2018, Pages 227-229

https://doi.org/10.1016/j.tibs.2018.02.006 Get rights and content

G-protein-coupled receptors (GPCRs) are the targets for many drugs, but the response shows interindividual variability. The ‘one-drug-fits-all’ approach has been challenged by evidence showing multiple human genetic variants of GPCRs. Identification and characterization of GPCR variants must be undertaken for rational, personalized, and economically sound prescribing practices.

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Cited by (2)

Personalized Medicine Through GPCR Pharmacogenomics
2022, Comprehensive Pharmacology
Understanding the magnitude of response to a given treatment at an individual level is one of the most important and long-standing challenges in personalized medicine and pharmacogenomics. A great deal of effort has been placed on understanding variation in drug transport and metabolism. However, little is known about how variability in receptor drug targets affects treatment regimens. G protein-coupled receptors (GPCRs) are the single most prevalent drug target family. Elucidating the spectrum and impact of how a GPCR variant influences ligand binding, signaling and, ultimately, therapeutic effect is vital and could serve as the next important step for understanding variability in drug response.
His452Tyr polymorphism in the human 5-HT<inf>2A</inf> receptor affects clozapine-induced signaling networks revealed by quantitative phosphoproteomics
2021, Biochemical Pharmacology
Citation Excerpt :
Single nucleotide polymorphisms resulting in the substitution of an amino acid in the primary structure of a given protein may confer alterations in its functionality at the physiological level. Particularly in the case of GPCRs, these polymorphisms could involve pharmacological implications such as alterations in the risk of developing a disease and/or alterations of the response to therapy [31]. One of the genetic variants of the human 5-HT2AR is a non-synonymous single nucleotide polymorphism consisting in the mutation C/T (rs6314) that results in the substitution His/Tyr at the position 452 of the amino acidic sequence of this protein.
Antipsychotic drugs remain the current standard for schizophrenia treatment. Although they directly recognize the orthosteric binding site of numerous monoaminergic G protein-coupled receptors (GPCRs), these drugs, and particularly second-generation antipsychotics such as clozapine, all have in common a very high affinity for the serotonin 5-HT_2A receptor (5-HT_2AR). Using classical pharmacology and targeted signaling pathway assays, previous findings suggest that clozapine and other atypical antipsychotics behave principally as 5-HT_2AR neutral antagonists and/or inverse agonists. However, more recent findings showed that antipsychotics may also behave as pathway-specific agonists. Reversible phosphorylation is a common element in multiple signaling networks. Combining a quantitative phosphoproteomic method with signaling network analysis, we tested the effect of clozapine treatment on the overall level of protein phosphorylation and signal transduction cascades in vitro in mammalian cell lines induced to express either the human 5-HT_2AR or the H452Y variant of the gene encoding the 5-HT_2AR receptor. This naturally occurring variation within the 5-HT_2AR gene was selected because it has been repeatedly associated with schizophrenia patients who do not respond to clozapine treatment. Our data show that short time exposure (5 or 10 min) to clozapine (10⁻⁵ M) led to phosphorylation of numerous signaling components of pathways involved in processes such as endocytosis, ErbB signaling, insulin signaling or estrogen signaling. Cells induced to express the H452Y variant showed a different basal phosphoproteome, with increases in the phosphorylation of mTOR signaling components as a translationally relevant example. However, the effect of clozapine on the functional landscape of the phosphoproteome was significantly reduced in cells expressing the 5-HT_2AR-H452Y construct. Together, these findings suggest that clozapine behaves as an agonist inducing phosphorylation of numerous pathways downstream of the 5-HT_2AR, and that the single nucleotide polymorphism encoding 5-HT_2AR-H452Y affects these clozapine-induced phosphorylation-dependent signaling networks.

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Trends in Biochemical Sciences

SpotlightGenetic Vulnerability of GPCRs: A Call to Action

Lancet

Pharmacogenomics of GPCR drug targets

Cell

Pharmacology and physiology of human adrenergic receptor polymorphisms

Annu. Rev. Pharmacol. Toxicol.

Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects

Am. J. Respir. Cell Mol. Biol.

Polymorphisms of the β2-adrenergic receptor determine exercise capacity in patients with heart failure

Circ. Res.

Spotlight
Genetic Vulnerability of GPCRs: A Call to Action

Polymorphisms of the β₂-adrenergic receptor determine exercise capacity in patients with heart failure