Kinins promote B2 receptor endocytosis and delay constitutive B1 receptor endocytosis.
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. In this study, we show that kinins modulate receptor endocytosis to rapidly decrease B2R and increase B1R on the cell surface. B2Rs, 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, B1Rs, 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. It is noteworthy that 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.
Enquist
Johan
J
Department of Experimental Medical Science, Lund University, BMC, A12, S-22184 Lund, Sweden.
Skröder
Carl
C
Whistler
Jennifer L
JL
Leeb-Lundberg
L M Fredrik
LM
D019390:Arrestins / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D022163:Clathrin-Coated Vesicles; D004705:Endocytosis / Q000187:drug effects*; D006801:Humans; D007705:Kinins / Q000494:pharmacology*; D021381:Protein Transport; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000502:physiology*; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; D019390:Arrestins; D007705:Kinins; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins