Control of the Cardiac Muscarinic K+ Channel by β-Arrestin 2

Abstract

Control of the cardiac muscarinic K+K' current (i K,ACh) by β-arrestin 2 has been studied. In Chinese hamster ovary cells transfected with m2 muscarinic receptor, muscarinic K+ channel, receptor kinase (GRK2), and β-arrestin 2, desensitization of iK,ACh during a 3-min application of 10 μM ACh was significantly increased as compared with that in cells transfected with receptor, channel, and GRK2 only (fade in current increased from 45 to 78%). The effect of β-arrestin 2 was lost if cells were not co-transfected with GRK2. Resensitization (recovery from desensitization) of iK,ACh in cells transfected with β-arrestin 2 was significantly slowed (time constant increased from 34 to 232 s). Activation and deactivation of iK,ACh on application and wash-off of ACh in cells transfected with β-arrestin 2 were significantly slowed from 0.9 to 3.1 s (time to half peak i K,ACh) and from 6.2 to 13.8 s (time to half-deactivation), respectively. In cells transfected with a constitutively active β-arrestin 2 mutant, desensitization occurred in the absence of agonist (peak current significantly decreased from 0.4 ± 0.05 to 0.1 ± 0.01 nA). We conclude that β-arrestin 2 has the potential to play a major role in desensitization and other aspects of the functioning of the muscarinic K + channel.