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

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 β-adrenergic agonists. The study's aims were to elucidate the mechanisms by which exercise training alters β-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 β-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 β₁-adrenergic receptor content but reduced the kinase anchoring protein yotiao and β-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 β-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 β-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_ATP channel, results in a more efficient heart that is better able to respond to beat-by-beat changes in metabolism.