title: Short-term desensitization of muscarinic K+ current in the heart.
abstract: Acetylcholine (ACh) rapidly increases cardiac K(+) currents (IKACh) by activating muscarinic K(+) (KACh) channels followed by a gradual amplitude decrease within seconds. This phenomenon is called short-term desensitization and its precise mechanism and physiological role are still unclear. We constructed a mathematical model for IKACh to examine the conditions required to reconstitute short-term desensitization. Two conditions were crucial: two distinct muscarinic receptors (m2Rs) with different affinities for ACh, which conferred an IKACh response over a wide range of ACh concentrations, and two distinct KACh channels with different affinities for the G-protein βγ subunits, which contributed to reconstitution of the temporal behavior of IKACh. Under these conditions, the model quantitatively reproduced several unique properties of short-term desensitization observed in myocytes: 1), the peak and quasi-steady states with 0.01-100 μM [ACh]; 2), effects of ACh preperfusion; and 3), recovery from short-term desensitization. In the presence of 10 μM ACh, the IKACh model conferred recurring spontaneous firing after asystole of 8.9 s and 10.7 s for the Demir and Kurata sinoatrial node models, respectively. Therefore, two different populations of KACh channels and m2Rs may participate in short-term desensitization of IKACh in native myocytes, and may be responsible for vagal escape at nodal cells.
authors.affiliation: Division of Molecular and Cellular Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Osaka, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan. Electronic address: murakami@pharma2.med.osaka-u.ac.jp.
authors.forename: Shingo
authors.initials: S
authors.lastname: Murakami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inanobe
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kurachi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000200:Action Potentials; D055724:Electrophysiological Phenomena; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D013997:Time Factors; D055536:Vagus Nerve Stimulation
chemical_list: D011976:Receptors, Muscarinic; D019204:GTP-Binding Proteins; D000109:Acetylcholine; D011188:Potassium
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