Molecular insights into the regulation of constitutive activity by RNA editing of 5HT2C serotonin receptors
Ryan H. Gumpper, Jonathan F. Fay, Bryan L. Roth
Cell Reports August 1, 2022 DOI: 10.1016/j.celrep.2022.111211 via OpenAlex
Summary
AI-generated from the abstractThe serotonin 2C receptor, a G protein-coupled receptor (GPCR) targeted by drugs like the weight-loss medication lorcaserin and the psychedelic psilocin, exists in many protein isoforms due to RNA editing. This study presents the structures of three representative isoforms bound to each drug and analyzes agonist activation and constitutive activity across all 24 isoforms. A unique hydrogen-bonding network on intracellular loop 2, which is altered by RNA editing, differentially affects the receptor's constitutive and agonist signaling activities.
Study at a glance
| Characteristics | Structural biology and biochemical analysis Peer reviewed |
|---|---|
| Keywords | Rna editing Gene isoform G protein-coupled receptor Inverse agonist Cell biology |
| Citations | 49 |
| Key finding | RNA editing of intracellular loop 2 creates a hydrogen-bonding network that differentially modulates GPCR constitutive and agonist signaling activities across all 24 isoforms of the serotonin 2C receptor. |
Abstract
-transducer-coupled structures of three representative isoforms (INI, VGV, and VSV) with the selective drug lorcaserin (Belviq) and the classic psychedelic psilocin. We also provide a comprehensive analysis of agonist activation and constitutive activity across all 24 protein isoforms. Collectively, these findings reveal a unique hydrogen-bonding network located on intracellular loop 2 that is subject to RNA editing, which differentially affects GPCR constitutive and agonist signaling activities.