Role of internalization of M2muscarinic receptor via clathrin-coated vesicles in desensitization of the muscarinic K+current in heart

Abstract

In the heart, ACh activates the ACh-activated K+current ( IK,ACh) via the M2muscarinic receptor. The relationship between desensitization of IK,AChand internalization of the M2receptor has been studied in rat atrial cells. On application of the stable muscarinic agonist carbachol for 2 h, IK,AChdeclined by ∼62% with time constants of 1.5 and 26.9 min, whereas ∼83% of the M2receptor was internalized from the cell membrane with time constants of 2.9 and 51.6 min. Transfection of the cells with β-adrenergic receptor kinase 1 (G protein-receptor kinase 2) and β-arrestin 2 significantly increased IK,AChdesensitization and M2receptor internalization during a 3-min application of agonist. Internalized M2receptor in cells exposed to carbachol for 2 h was colocalized with clathrin and not caveolin. It is concluded that a G protein-receptor kinase 2- and β-arrestin 2-dependent internalization of the M2receptor into clathrin-coated vesicles could play a major role in IK,AChdesensitization.