Faculty Collaboration Database

Cardiomyocyte slowly activating delayed rectifier potassium channel: regulation by exercise and β-adrenergic signaling. J Appl Physiol (1985) 2020 May 01;128(5):1177-1185

Date

04/03/2020

Pubmed ID

32240024

DOI

10.1152/japplphysiol.00802.2019

Scopus ID

2-s2.0-85084167515 (requires institutional sign-in at Scopus site)   7 Citations

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 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.

Author List

Wang X, Fitts RH

Authors

Robert Fitts PhD Professor in the Biological Sciences department at Marquette University
Xinrui Wang Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

A Kinase Anchor Proteins
Action Potentials
Adrenergic Agents
Animals
Cytoskeletal Proteins
KCNQ1 Potassium Channel
Motor Activity
Myocytes, Cardiac
Physical Conditioning, Animal
Potassium Channels, Voltage-Gated
Rats