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. 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 β-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 β-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.