Internalization of G-protein-coupled receptors: Implication in receptor function, physiology and diseases

Abstract

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and mediate the effects of numerous hormones and neurotransmitters. The nearly 1000 GPCRs encoded by the human genome regulate virtually all physiological functions and are implicated in the pathogenesis of prevalent human diseases such as thyroid disorders, hypertension or Parkinson's disease. As a result, 30-50% of all currently prescribed drugs are targeting these receptors. Once activated, GPCRs induce signals at the cell surface. This is often followed by internalization, a process that results in the transfer of receptors from the plasma membrane to membranes of the endosomal compartment. Internalization was initially thought to be mainly implicated in signal desensitization, a mechanism of adaptation to prolonged receptor stimulation. However, several unexpected functions have subsequently emerged. Most notably, accumulating evidence indicates that internalization can induce prolonged receptor signaling on intracellular membranes, which is apparently required for at least some biological effects of hormones like TSH, LH and adrenaline. These findings reveal an even stronger connection between receptor internalization and signaling than previously thought. Whereas new studies are just beginning to reveal an important physiological role for GPCR signaling after internalization and ways to exploit it for therapeutic purposes, future investigations will be required to explore its involvement in human disease.

Exploring Biased Agonism at FPR1 as a Means to Encode Danger Sensing

“…Relative potencies and efficacies of the analyzed agonists differed significantly in our assay ( Figure 2). Bacterial peptides [31,32] and the W-peptide [15,33,34], formed a distinct group of agonists with high potencies and efficacies, mitochondrial peptides-on the other hand-were characterized by significantly lower potencies. However, differences in the respective efficacies for bacterial and mitochondrial peptides were not as pronounced.…”

“…Receptor internalization, which is linked with desensitization and signal termination, is regulated via GPCR/agonist interactions. Notably, emerging novel findings suggest that this mechanism might also be linked to prolonged receptor signaling [15,16].Here, we compared the signaling profiles of representative microbial, endogenous, and synthetic FPR1 agonists. Our results reveal that the FPR1 activators cluster depending on their origin: the bacterial formylated peptides are strong, potent, and efficacious superagonists, whereas the mitochondrial peptides are less effective.…”

“…Receptor internalization, which is linked with desensitization and signal termination, is regulated via GPCR/agonist interactions. Notably, emerging novel findings suggest that this mechanism might also be linked to prolonged receptor signaling [15,16].…”

Model‐free and kinetic modelling approaches for characterising non‐equilibrium pharmacological pathway activity: Internalisation of cannabinoid CB1 receptors

“…Receptor theory has long recognised cell surface receptor density as a critical factor for determining the magnitude (efficacy) of receptor‐mediated signalling responses (Black & Leff, ; Furchgott, ). For GPCRs, internalisation is a commonly used pharmacological “signalling” end point and receptor internalisation as a mechanism to decrease cell responsiveness to agonists is now seen as a critical component of both the regulation of physiological GPCR function and prevention of toxic system overstimulation (Calebiro & Godbole, ; Hanyaloglu & von Zastrow, ; von Zastrow, ).…”

“…component of both the regulation of physiological GPCR function and prevention of toxic system overstimulation (Calebiro & Godbole, 2018;Hanyaloglu & von Zastrow, 2008;von Zastrow, 2003).…”