Endocytosis and recycling of G protein-coupled receptors

doi:10.1016/S0165-6147(97)01091-2

Trends in Pharmacological Sciences

Volume 18, Issue 8, 1 August 1997, Pages 276-287

https://doi.org/10.1016/S0165-6147(97)01091-2 Get rights and content

Abstract

Agonist stimulation of G protein-coupled receptors causes a dramatic reorganization of their intracellular distribution. Activation of receptors triggers receptor endocytosis and, since receptors recycle back to the surface continuously, a new steady state is reached where a significant proportion of receptors is located internally. Although this movement of receptors is remarkable, its role has been enigmatic. Recent developments have provided insight into the compartments through which the receptors move, the nature of the signals that trigger receptor translocation, and the significance of receptor cycling for cell function. In this article, Jennifer Koenig and Michael Edwardson review recent progress in this field and place receptor cycling into a mathematical framework that reveals the extent and rate of intracellular receptor movement.

Section snippets

Measurement of the internalization of receptors and ligands

The methodology used to determine changes in intracellular receptor distribution varies with the receptor type and the available experimental tools. For receptors where membrane-impermeant antagonist radioligands are available, changes in surface receptor number can be measured through changes in the radioligand binding site density[1]. In these experiments (Fig. 2a), the cells are treated with agonist drug for varying times at 37°C, washed thoroughly, and then incubated at low temperatures

Two-compartment model

It is possible to estimate the number of receptors cycling to and from the plasma membrane using kinetic modelling based on a simple two-compartment model. The modelling makes no assumptions about whether the ligand is endocytosed with the receptor—it is assumed only that application of agonist dramatically and instantaneously increases the rate of endocytosis of the receptor. It can be shown mathematically (see Appendix B) that the number of surface receptors and the number of endosomal

Endocytosis motifs

Receptor endocytosis has been best characterized for receptors for polypeptides such as low density lipoprotein (LDL) and transferrin. Here, the purpose of endocytosis is to capture the ligand for subsequent use by the cell. The receptors cycle continuously between the cell surface and endosomes, binding ligand at the cell surface and depositing it in endosomes. Mutational analysis of the endocytosis of these receptors has led to the proposition that aromatic residues in two sequence motifs in

Desensitization and resensitization

It might seem reasonable to propose that receptor internalization plays a role in desensitization, with a fall in the numbers of G protein-coupled receptors at the plasma membrane causing a reduction in the cellular response to agonist. However, loss of receptors from the surface is usually too slow to account for the rapid onset of desensitization[48], and there are cases where the drop in surface receptor number occurs without desensitization[49], and vice versa[50]. Finally, inhibition of

Concluding remarks

At present, the G protein-coupled receptor superfamily has over 200 members. Although all of these receptors have a common membrane topology, there is little conservation of specific amino acid sequence across the whole superfamily and the variety of cellular responses initiated by the receptors is enormous. Much of the information available at present concerning the nature of the signals specifying endocytosis, and the consequences of receptor cycling for cell function, is derived from studies

Acknowledgements

The authors thank Dr P. G. Szekeres and Prof. P. P. A. Humphrey for helpful discussions. J. A. K. would like to thank Prof. P. P. A. Humphrey, Glaxo Institute of Applied Pharmacology and Magdalene College for encouragement and financial support. J. M. E. is grateful to the Wellcome Trust for financial support.

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Trends in Pharmacological Sciences

Endocytosis and recycling of G protein-coupled receptors

Abstract

Section snippets

Measurement of the internalization of receptors and ligands

Two-compartment model

Endocytosis motifs

Desensitization and resensitization

Concluding remarks

Acknowledgements

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