We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Nitrosylation of cardiac CaMKII at Cys290 mediates mechanical afterload‐induced increases in Ca<sup>2+</sup> transient and Ca<sup>2+</sup> sparks.
- Authors
Alim, Chidera C.; Ko, Christopher Y.; Mira Hernandez, Juliana; Shen, Erin Y.; Baidar, Sonya; Chen‐Izu, Ye; Bers, Donald M.; Bossuyt, Julie
- Abstract
Cardiac mechanical afterload induces an intrinsic autoregulatory increase in myocyte Ca2+ dynamics and contractility to enhance contraction (known as the Anrep effect or slow force response). Our prior work has implicated both nitric oxide (NO) produced by NO synthase 1 (NOS1) and calcium/calmodulin‐dependent protein kinase II (CaMKII) activity as required mediators of this form of mechano‐chemo‐transduction. To test whether a single S‐nitrosylation site on CaMKIIδ (Cys290) mediates enhanced sarcoplasmic reticulum Ca2+ leak and afterload‐induced increases in sarcoplasmic reticulum (SR) Ca2+ uptake and release, we created a novel CRISPR‐based CaMKIIδ knock‐in (KI) mouse with a Cys to Ala mutation at C290. These CaMKIIδ‐C290A‐KI mice exhibited normal cardiac morphometry and function, as well as basal myocyte Ca2+ transients (CaTs) and β‐adrenergic responses. However, the NO donor S‐nitrosoglutathione caused an acute increased Ca2+ spark frequency in wild‐type (WT) myocytes that was absent in the CaMKIIδ‐C290A‐KI myocytes. Using our cell‐in‐gel system to exert multiaxial three‐dimensional mechanical afterload on myocytes during contraction, we found that WT myocytes exhibited an afterload‐induced increase in Ca2+ sparks and Ca2+ transient amplitude and rate of decline. These afterload‐induced effects were prevented in both cardiac‐specific CaMKIIδ knockout and point mutant CaMKIIδ‐C290A‐KI myocytes. We conclude that CaMKIIδ activation by S‐nitrosylation at the C290 site is essential in mediating the intrinsic afterload‐induced enhancement of myocyte SR Ca2+ uptake, release and Ca2+ transient amplitude (the Anrep effect). The data also indicate that NOS1 activation is upstream of S‐nitrosylation at C290 of CaMKII, and that this molecular mechano‐chemo‐transduction pathway is beneficial in allowing the heart to increase contractility to limit the reduction in stroke volume when aortic pressure (afterload) is elevated. Key points: A novel CRISPR‐based CaMKIIδ knock‐in mouse was created in which kinase activation by S‐nitrosylation at Cys290 (C290A) is prevented.How afterload affects Ca2+ signalling was measured in cardiac myocytes that were embedded in a hydrogel that imposes a three‐dimensional afterload.This mechanical afterload induced an increase in Ca2+ transient amplitude and decay in wild‐type myocytes, but not in cardiac‐specific CaMKIIδ knockout or C290A knock‐in myocytes.The CaMKIIδ‐C290 S‐nitrosylation site is essential for the afterload‐induced enhancement of Ca2+ transient amplitude and Ca2+ sparks.
- Subjects
NITROSYLATION; NITRIC-oxide synthases; SARCOPLASMIC reticulum; CALCIUM ions; PROTEIN kinases
- Publication
Journal of Physiology, 2022, Vol 600, Issue 22, p4865
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/JP283427