Receptor Internalisation
Receptor internalisation is the agonist-driven removal of receptors from the cell surface into endosomes, a step that can end in recycling, in degradation, or in continued signalling from inside the cell.
After an agonist-occupied receptor is phosphorylated and bound by beta-arrestin, the complex is drawn into clathrin-coated pits and pinched off into endosomes. What follows is a sorting decision. Receptors that release arrestin quickly are dephosphorylated and returned to the surface within minutes, restoring responsiveness. Receptors holding arrestin in a stable complex recycle slowly or go to lysosomes, turning a transient removal into lasting loss of surface receptor.
Internalisation is not the simple off switch it was once assumed to be. Several GPCRs, the GLP-1 receptor among them, have been reported to keep generating cAMP from endosomal compartments after leaving the membrane. It is also exploited directly: somatostatin receptor internalisation carries a radiolabelled peptide into a neuroendocrine tumour cell, the basis of lutetium-177 dotatate, approved in 2018 on the NETTER-1 trial.
Whether an agonist drives internalisation is a design variable rather than a defect. Agonists biased toward G protein coupling over arrestin recruitment internalise less and may sustain surface signalling longer; agonists that internalise strongly are preferred when the goal is delivery into the cell. Reading it correctly means knowing which a compound does, and at what exposure.
The persistent confusion is between internalisation and downregulation. Internalisation is a trafficking event measured in minutes and usually reversible; downregulation is a net loss of total receptor requiring resynthesis. An assay showing surface receptor disappearing says nothing about whether those receptors were destroyed or returned, and a compound called non-internalising on a short imaging experiment has not been shown to spare receptor number across a dosing interval.