ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Commun 2017;8:443

G-protein-coupled receptors (GPCRs) are a large family of receptors localized at the cell membrane, detecting specific ligands such as hormones, neurotransmitters, odors, pheromones. Further, GCPRs are the main element for the photoisomerization process, necessary to convert a photon impulse to an electrical signal in photosensitive ganglion cells of the retina. GCPRs are involved in a large spectrum of physiological processes and disordered GPCR function causes a variety of human diseases¹. Extracellular binding of specific ligands to GCPRs leads to conformational changes of the GCPRs, activation of the G-proteins at the internal side of the cell membrane and activation of intracellular signaling pathways, which are the cAMP/PKA signaling pathway and the phosphatidylinositol signaling pathway.

While the first steps of GCPR activation at the cell membrane are well characterized, recent data suggested that GCPRs could be internalized in different intracellular compartments. More specifically, the observation of co-localized TSH/TSHR complexes with G-protein in the Golgi apparatus raised the question whether GPCR signaling might be active not only in the early endosomal compartment close to the inner side of the cell membrane but also in other intracellular compartments.

To address this aspect of GCPR physiology, here Godbole et al. performed an elegant study directly visualizing the whole process of ligand binding at the cell surface, internalization and activation of the TSH/TSHR G-protein complex, and its intracellular trafficking by quantification of cAMP/PKA signaling during this whole process. The authors propose a compartmentalized model of TSHR signaling: Internalization of TSH/TSHR complex on binding into an early endosomal compartment, retrograde trafficking of TSH/TSHR complex within the endosome to the Golgi apparatus, G-protein activation only in close contact of the TSH/TSHR G-protein containing endosome close to the Golgi apparatus, and cAMP/PKA signaling at the Golgi apparatus only near the nucleus. Further, the authors showed that the retrograde trafficking of the TSHR was required for efficient PKA-dependent nuclear phosphorylation of the cAMP response element binding protein (CREB), and TSH-induced gene expression. In summary, the authors show functional evidence for multiple intracellular sites of GCPR signaling, providing new insights into GCPR physiology and opening new avenues for pharmaceutical research.

1. Weis WI, Kobilka BK. The molecular basis of G protein coupled receptor activation. Annu Rev Biochem 2018;87:897-919.