Abstract
Cardiac function is controlled by autonomic nervous system. The released ACh decelerates the heart beat and delays the artrio-ventricular conduction. This is due to activation of K+ channels in nodal cells first identified by Prof. Sunao Tawara in 1906. The ACh-deceleration of heart beat is the first example of synaptic chemical transmission revealed by Prof. Otto Levi in 1920s. It is a great honor for me to talk about its ionic mechanism, i.e., muscarinic activation of cardiac K+ channel, on which I have been working for more than 20 years. In cardiac nodal and atrial myocytes, application of ACh elicits a KACh current. The KACh channel comprises Kir3.1 and Kir3.4. The activation time-course is sigmoidal and takes several hundred ms to reach a peak. Thereafter, the current decreases to a quasi-steady state level in 1 min in the presence of ACh. When I started studying activation mechanism of KACh channel by ACh, I observed three phenomena; 1) rapid run-down of the response, 2) the short term-desensitization, and 3) the agonist-dependent relaxation of the current. We found wash-out of intracellular GTP caused rapid rundown because the channel is activated by PTX-sensitive G proteins. We for the first time clarified that the βγ subunit of G proteins directly activates the channel. We have recently revealed the agonist-dependent relaxation of KACh current is caused by the voltage-dependent action of RGS proteins, which facilitates GTPase activity of Gα. On the basis of these results, we could have modeled physiological behavior of G protein-activation of KACh channel. [Jpn J Physiol 55 Suppl:S4 (2005)]
