Cardiomyocyte slowly activating delayed rectifier potassium channel: regulation by exercise and β-adrenergic signaling

Exercise training is known to prolong the ventricular cardiomyocyte action potential duration (APD). increasing Ca2+ influx and contractility. The prolonged APD is caused, in part, by a decreased responsiveness to beta-adrenergic agonists. The study's aims were to elucidate the mechanisms by which exercise training alters I3-adrenergic regulation and to determine the involvement of delayed rectifier potassium channels (I-Kr and I-Ks) in the response. Rats were randomly assigned to wheel running-trained (TRN) or sedentary (SED) groups. After 6-8 wk of training, myocytes were isolated from the apex and base regions of the left ventricle, and current-voltage relationships of I-Kr and I-Ks were measured. Myocytes from SED and TRN rats exhibit lower I-Kr current compared with I-Ks, and a regional difference in I-Ks was observed, with higher current in apex compared with base myocytes. Wheel running decreased I-Ks at positive voltages and reduced I-Ks responsiveness to beta-agonist. I-Ks channel subunit KCNQ1 content was higher in apex compared with base, and exercise training decreased KCNQ1 and KCNE1 subunit content in both regions. Exercise training had no effect on beta(1)-adrenergic receptor content but reduced the kinase anchoring protein yotiao and beta-adrenergic receptor kinase GRK2 compared with SED rats. The reduced KCNQ1, KCNE1, and yotiao provide a mechanism underlying the training-induced decrease in I-Ks current, while downregulation of GRK2 would reduce inactivation of the beta-AR, maintaining adrenergic stimulation of contractility. Collectively, these membrane protein changes in response to TRN provide a mechanism for prolonging the APD, increasing myocyte efficiency in low stress conditions, while increasing contractility. NEW & NOTEWORTHY Results demonstrate that exercise training (TRN) downregulates ventricular I-Ks channel current and the channel's responsiveness to beta-agonist factors mediated by TRN-induced decline in channel subunits KCNQ1 and KCNE1 and the A-kinase anchoring protein yotiao. The reduced I-Ks current helps explain the TRN-induced prolongation of the action potential in basal conditions and, coupled with previously reported upregulation of the K A(TP) channel, results in a more efficient heart that is better able to respond to beat-by-beat changes in metabolism.