title: Constitutive activity of the acetylcholine-activated potassium current IK,ACh in cardiomyocytes.
abstract: Stimulation of the vagal nerve slows the heart rate and leads to shorter action potential duration in the atria. These effects are mainly mediated by binding of the vagal neurotransmitter acetylcholine to muscarinic type 2 receptors resulting in dissociation of Gi proteins and subsequent activation of IK,ACh-K(+) channels due to binding of Gβγ-subunits. Even though agonist-independent (constitutive) IK,ACh activity is considered negligible in the healthy heart, constitutive IK,ACh activity has been shown to contribute to remodeling processes associated with cardiac diseases such as atrial fibrillation. In this review, we summarize possible mechanisms, which may contribute to the development of constitutively active IK,ACh. For example, an increased availability of Gβγ-subunits within the IK,ACh channel complex could contribute to receptor-independent IK,ACh activation. Accordingly, reduced expression of Gα-subunits, which act as Gβγ-scavengers within the channel complex, and increased activity of nucleoside diphosphate kinases, which activate G proteins in a receptor-independent manner, are likely contributors to constitutively active IK,ACh. In addition, alterations of the IK,ACh channel composition or phosphorylation may also be involved in abnormal IK,ACh current activity. Finally, we discuss possible therapeutic applications of pharmacological IK,ACh modulators, which may represent future drug targets against cardiac diseases such as atrial fibrillation.
authors.affiliation: Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany.
authors.forename: Issam
authors.initials: I
authors.lastname: Abu-Taha
authors.affiliation: Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany.
authors.forename: Jordi
authors.initials: J
authors.lastname: Heijman
authors.affiliation: Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany. Electronic address: dobromir.dobrev@uk-essen.de.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D006801:Humans; D015640:Ion Channel Gating; D058990:Molecular Targeted Therapy; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*
chemical_list: D015221:Potassium Channels; D000109:Acetylcholine
keywords: Atrial fibrillation; Constitutive activity; G proteins; GIRK; I(K,ACh); M(2) receptor; Muscarinic receptor; NDPK; Nucleoside diphosphate kinase; Remodeling