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First published on November 16, 2006; DOI: 10.1124/mol.106.030858

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Received for publication September 13, 2006.
Revised November 16, 2006.
Accepted for publication November 16, 2006.

KININS PROMOTE B2 RECEPTOR ENDOCYTOSIS AND DELAY CONSTITUTIVE B1 RECEPTOR ENDOCYTOSIS

Johan Enquist 1, Carl Skroder 1, Jennifer L. Whistler 2, Fredrik L.M. Leeb-Lundberg 1*

1 Lund University 2 University of California, San Francisco

* Address correspondence to: E-mail: fredrik.leeb-lundberg{at}med.lu.se

Abstract

Upon sustained insult, kinins are released and many kinin responses, such as inflammatory pain, adapt from a B2 receptor (B2R)-type in the acute phase to a B1 receptor (B1R)-type in the chronic phase. Here, we show that kinins modulate receptor endocytosis to rapidly decrease B2R and increase B1R on the cell surface. B2R, which require agonist for activity, are stable plasma membrane components without agonist but recruit {beta}-arrestin 2, internalize in a clathrin-dependent manner, and recycle rapidly upon agonist treatment. In contrast, B1R, which are inducible and constitutively active, constitutively internalize without agonist via a clathrin-dependent pathway, do not recruit {beta}-arrestin 2, bind G protein-coupled receptor sorting protein, and target lysosomes for degradation. Agonist delays B1R endocytosis, thus transiently stabilizing the receptor. Most of the receptor trafficking phenotypes are transplantable from one receptor to the other through exchange of the C-terminal receptor tails, indicating that the tails contain epitopes that are important for the binding of protein partners that participate in the endocytic and postendocytic receptor choices. Interestingly, the agonist delay of B1R endocytosis is not transplanted to the B2R via the B1R tail, suggesting that this property of the B1R requires another domain. These events provide a rapid kinin-dependent mechanism for 1) regulating the constitutive B1R activity and 2) shifting the balance of accessible receptors in favor of B1R.


Key words: Bradykinin, Sequestration/Internalization, Receptor degradation, Recycling, Fluorescence techniques


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