| Title: |
PKA phosphorylation underlies functional recruitment of sarcolemmal SK2 channels in ventricular myocytes from hypertrophic hearts |
| Authors: |
Hamilton, Shanna; Polina, Iuliia; Terentyeva, Radmila; Bronk, Peter; Kim, Tae Yun; Roder, Karim; Clements, Richard T.; Koren, Gideon; Choi, Bum‐Rak; Terentyev, Dmitry |
| Contributors: |
National Heart, Lung, and Blood Institute; American Heart Association |
| Source: |
The Journal of Physiology ; volume 598, issue 14, page 2847-2873 ; ISSN 0022-3751 1469-7793 |
| Publisher Information: |
Wiley |
| Publication Year: |
2019 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
Key points Small‐conductance Ca 2+ ‐activated K + (SK) channels expressed in ventricular myocytes are dormant in health, yet become functional in cardiac disease. SK channels are voltage independent and their gating is controlled by intracellular [Ca 2+ ] in a biphasic manner. Submicromolar [Ca 2+ ] activates the channel via constitutively‐bound calmodulin, whereas higher [Ca 2+ ] exerts inhibitory effect during depolarization. Using a rat model of cardiac hypertrophy induced by thoracic aortic banding, we found that functional upregulation of SK2 channels in hypertrophic rat ventricular cardiomyocytes is driven by protein kinase A (PKA) phosphorylation. Using site‐directed mutagenesis, we identified serine‐465 as the site conferring PKA‐dependent effects on SK2 channel function. PKA phosphorylation attenuates I SK rectification by reducing the Ca 2+ /voltage‐dependent inhibition of SK channels without changing their sensitivity to activating submicromolar [Ca 2+ ] i . This mechanism underlies the functional recruitment of SK channels not only in cardiac disease, but also in normal physiology, contributing to repolarization under conditions of enhanced adrenergic drive. Abstract Small‐conductance Ca 2+ ‐activated K + (SK) channels expressed in ventricular myocytes (VMs) are dormant in health, yet become functional in cardiac disease. We aimed to test the hypothesis that post‐translational modification of SK channels under conditions accompanied by enhanced adrenergic drive plays a central role in disease‐related activation of the channels. We investigated this phenomenon using a rat model of hypertrophy induced by thoracic aortic banding (TAB). Western blot analysis using anti‐pan‐serine/threonine antibodies demonstrated enhanced phosphorylation of immunoprecipitated SK2 channels in VMs from TAB rats vs . Shams, which was reversible by incubation of the VMs with PKA inhibitor H89 (1 μmol L –1 ). Patch clamped VMs under basal conditions from TABs but not Shams exhibited outward current sensitive to the specific ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1113/jp277618 |
| DOI: |
10.1113/JP277618 |
| Availability: |
https://doi.org/10.1113/jp277618; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1113%2FJP277618; https://onlinelibrary.wiley.com/doi/pdf/10.1113/JP277618; https://onlinelibrary.wiley.com/doi/full-xml/10.1113/JP277618; https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP277618 |
| Rights: |
http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.AFF79CD4 |
| Database: |
BASE |