Orphan GPCRs

Orphan G protein-coupled receptors, or "orphan GPCRs" for short, are a special class of G protein-coupled receptors for which the natural activating ligand is not known. - In this respect, the term "orphan" was coined for this type of receptor. These receptors can nevertheless be active - either through constitutive activity or through the binding of artificial ligands in research studies. Some formerly "orphan" GPCRs have now been "de-orphanized", i.e. the natural ligands have been found and their functions discovered.

For example, the orphan GPCRs include the receptors GPR55, GPR119 and GPR18 . They are all associated with the endocannabinoid system, metabolism or pain regulation, for example.

The orphan G protein-coupled receptor Mrgpra2a/b is expressed on neutrophil granulocytes and activated by antimicrobial peptides/defensins. This signaling axis is required, for example, for effective neutrophil-mediated skin immunity and microbiome hemoostasis.

G protein-coupled receptors (GPCRs) are a large family of membrane receptors on cell surfaces that respond to external stimuli (e.g. hormones, neurotransmitters, light, odors). They are involved in many physiological processes and activate so-called G proteins after ligand binding, which trigger intracellular signaling cascades.

1. Dong X et al. (2022) Keratinocyte-derived defensins activate neutrophil-specific receptors Mrgpra2a/b to prevent skin dysbiosis and bacterial infection. Immunity 55:1645-1662.e7.