Short-Term Desensitization of Muscarinic K+ Current in the Heart

Acetylcholine (ACh) rapidly increases cardiac K+ currents (I-KACh) by activating muscarinic K+ (K-ACh) 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 I-KACh to examine the conditions required to reconstitute short-term desensitization. Two conditions were crucial: two distinct muscarinic receptors (m(2)Rs) with different affinities for ACh, which conferred an I-KACh response over a wide range of ACh concentrations, and two distinct K-ACh channels with different affinities for the G-protein beta gamma subunits, which contributed to reconstitution of the temporal, behavior of I-KACh. 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 mu M [ACh]; 2), effects of ACh preperfusion; and 3), recovery from short-term desensitization. In the presence of 10 mu M ACh, the I-KACh 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 K-ACh channels and m(2)Rs may participate in short-term desensitization of I-KACh in native myocytes, and may be responsible for vagal escape at nodal cells.