Isoforms of GPR35 have distinct extracellular N-termini that allosterically modify receptor-transducer coupling and mediate intracellular pathway bias
Hannes Schihada, Thomas M. Klompstra, Laura J. Humphrys, Igor Červenka, Shamim Dadvar, Peter Kolb, Jorge L. Ruas, Gunnar Schulte
Abstract
activation, while an additional cysteine contributed by the extended N-terminus of the long GPR35 isoform limits the extent of agonist-induced receptor-β-arrestin2 interaction. The pharmacological profiles and mechanistic insights of our study provide clues for the future design of isoform-specific GPR35 ligands that selectively modulate GPR35-transducer interactions and allow for mechanism-based therapies against, for example, inflammatory bowel disease or bacterial infections of the gastrointestinal system.
Topics & Concepts
IntracellularExtracellularAllosteric regulationCell biologyChemistryGene isoformCoupling (piping)ReceptorProtein–protein interactionBiophysicsBiologyBiochemistryGeneMaterials scienceMetallurgyReceptor Mechanisms and SignalingDrug Transport and Resistance MechanismsNeuropeptides and Animal Physiology