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Am J Physiol Heart Circ Physiol 292: H1737-H1746, 2007. First published September 29, 2006; doi:10.1152/ajpheart.01287.2005
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Role of internalization of M2 muscarinic receptor via clathrin-coated vesicles in desensitization of the muscarinic K+ current in heart

T. T. Yamanushi,2,* Z. Shui,1,* R. N. Leach,3 H. Dobrzynski,1 T. W. Claydon,4 and M. R. Boyett1

1Cardiovascular Research Group, School of Medicine, University of Manchester, Manchester, United Kingdom; 2Kagawa Prefectural College of Health Sciences, Mure, Kagawa, Japan; 3Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom; and 4Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada

Submitted 7 December 2005 ; accepted in final form 27 September 2006

In the heart, ACh activates the ACh-activated K+ current (IK,ACh) via the M2 muscarinic receptor. The relationship between desensitization of IK,ACh and internalization of the M2 receptor has been studied in rat atrial cells. On application of the stable muscarinic agonist carbachol for 2 h, IK,ACh declined by ~62% with time constants of 1.5 and 26.9 min, whereas ~83% of the M2 receptor was internalized from the cell membrane with time constants of 2.9 and 51.6 min. Transfection of the cells with beta-adrenergic receptor kinase 1 (G protein-receptor kinase 2) and beta-arrestin 2 significantly increased IK,ACh desensitization and M2 receptor internalization during a 3-min application of agonist. Internalized M2 receptor 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 beta-arrestin 2-dependent internalization of the M2 receptor into clathrin-coated vesicles could play a major role in IK,ACh desensitization.

acethylcholine-activated potassium current; acetylcholine; Kir3.1; Kir3.4; caveolin


Address for reprint requests and other correspondence: M. R. Boyett, Cardiovascular Research Group, School of Medicine, Univ. of Manchester, Core Technology Facility, 46 Grafton St., Manchester M13 9NT, UK (e-mail: mark.boyett{at}manchester.ac.uk)






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