Abstract
Recycling of endocytosed G-protein-coupled receptors involves a series of molecular events through early and recycling endosomes. The purpose of this work was to study the role of neuron-enriched endosomal protein of 21 kDa (NEEP21) in the recycling process of neurotensin receptors-1 and -2. Here we showed that suppression of NEEP21 expression does not modify the internalization rate of both receptors but strongly inhibited the recycling of the neurotensin receptor-2. In contrast, overexpression of NEEP21 changes the behavior of the neurotensin receptor-1 from a non-recycling to a recycling state. Recycling of the neurotensin receptor-2 involves both the phosphatidylinositol 3-kinase and the recycling endosome pathways, whereas recycling of the neurotensin receptor-1 induced by overexpression of NEEP21 only occurs by the phosphatidylinositol 3-kinase-dependent pathway. Taken together, these results confirm the essential role of NEEP21 in the recycling mechanism and show that this protein acts at the level of early endosomes to promote sorting of receptors toward a recycling pathway.
Highlights
G-protein-coupled receptors (GPCR)1 activated by their agonists are sequestrated into intracellular compartments as ligand-receptor complexes
Nothing is known about its implication in the recycling processes of GPCRs internalized after activation by their ligands
By using the two identified NT receptors coupled to G-proteins as a model of recycling and non-recycling receptors, we established a crucial role for neuron-enriched endosomal protein of 21 kDa (NEEP21) in the modulation of the intracellular behavior of both receptors
Summary
G-protein-coupled receptors (GPCR) activated by their agonists are sequestrated into intracellular compartments as ligand-receptor complexes. Receptor recycling to the plasma membrane can be achieved either directly from early endosomes or through tubular vesicular recycling endosomes (REs) [3]. These two recycling pathways can be distinguished by their recycling rate, by their sensitivity to different drugs, and by the involvement of various small Rab GTPases. These two receptors can be distinguished by their different affinities for NT Both receptors are internalized upon NT activation, only the NTSR2 is able to recycle back to the plasma membrane [9, 10], with the NTSR1 being targeted to lysosomes [11] (for review see Ref. 12). We showed that endogenous NEEP21-dependent NTSR2 recycling and NEEP21-forced NTSR1 recycling take different intracellular pathways
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