β2-Adrenergic Receptor Internalization, Endosomal Sorting, and Plasma Membrane Recycling Are Regulated by Rab GTPases*

Abstract

Rab GTPases are recognized as critical regulatory factors involved in vesicular membrane transport and endosomal fusion. For example, Rab5 directs the transport and fusion of endocytic vesicles to and with early endosomes, whereas Rab4 is thought to control protein trafficking from early endosomes back to the plasma membrane. In the present study, we investigated the role of Rab5 and Rab4 GTPases in regulating the endocytosis, intracellular sorting, and the plasma membrane recycling of the β2AR. In cells expressing the dominant-negative Rab5-S34N mutant, β2AR internalization was impaired, and β2AR-bearing endocytic vesicles remained in either close juxtaposition or physically attached to the plasma membrane. In contrast, a constitutively active Rab5-Q79L mutant redirected internalized β2AR to enlarged endosomes but did not prevent β2AR dephosphorylation and recycling. The expression of either wild-type Rab4 or a Rab4-N121I mutant did not prevent β2AR dephosphorylation. However, the dominant-negative Rab4-N121I mutant blocked β2AR resensitization by blocking receptor recycling from endosomes back to the cell surface. Our data indicate that, in addition to regulating the intracellular trafficking and fusion of β2AR-bearing endocytic vesicles, Rab5 also contributes to the formation and/or budding of clathrin-coated vesicles. Furthermore, β2AR dephosphorylation occurs as the receptor transits between Rab5- and Rab4-positive compartments.

  • Abbreviations:
    GPCR
    G protein-coupled receptor
    β2AR
    β2-adrenergic receptor
    GFP
    green fluorescence protein
    HA
    hemagglutinin
    • Received May 1, 2000.
    • Revision received May 31, 2000.
    Table of Contents

    This Article

    1. The Journal of Biological Chemistry 275, 27221-27228.
    1. All Versions of this Article:
      1. M003657200v1
      2. 275/35/27221 (most recent)

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