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

ABSTRACT

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 ß-adrenergic agonists. The study's aims were to elucidate the mechanisms by which exercise training alters ß-adrenergic regulation and to determine the involvement of delayed rectifier potassium channels (IKr and IKs) 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 IKr and IKs were measured. Myocytes from SED and TRN rats exhibit lower IKr current compared with IKs, and a regional difference in IKs was observed, with higher current in apex compared with base myocytes. Wheel running decreased IKs at positive voltages and reduced IKs responsiveness to ß-agonist. IKs 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 ß1-adrenergic receptor content but reduced the kinase anchoring protein yotiao and ß-adrenergic receptor kinase GRK2 compared with SED rats. The reduced KCNQ1, KCNE1, and yotiao provide a mechanism underlying the training-induced decrease in IKs current, while downregulation of GRK2 would reduce inactivation of the ß-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 IKs channel current and the channel's responsiveness to ß-agonist factors mediated by TRN-induced decline in channel subunits KCNQ1 and KCNE1 and the A-kinase anchoring protein yotiao. The reduced IKs current helps explain the TRN-induced prolongation of the action potential in basal conditions and, coupled with previously reported upregulation of the KATP channel, results in a more efficient heart that is better able to respond to beat-by-beat changes in metabolism.