When NCX switches sides: experimental and computational insights into Ca(2+) regulation in the heart

Neubert, Wilhelm; Hüttemeister, Judith; Sander, Paulina; Chamakuri, Nagaiah; Hohendanner, Felix; Falcke, Martin; Heinzel, Frank R.

When NCX switches sides: experimental and computational insights into Ca(2+) regulation in the heart

Tools

Preview	PDF (Publisher's Version) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader 4MB
	Other (Supporting Information) 500kB

Item Type:	Article
Title:	When NCX switches sides: experimental and computational insights into Ca(2+) regulation in the heart
Creators Name:	Neubert, Wilhelm, Hüttemeister, Judith, Sander, Paulina, Chamakuri, Nagaiah, Hohendanner, Felix, Falcke, Martin and Heinzel, Frank R.
Abstract:	The Na(+)/Ca(2+) exchanger (NCX) transports Ca(2+) and Na(+) through the plasma membrane of cardiomyocytes. NCX dysregulation has been related to diastolic dysfunction. NCX inhibition has been identified as a potential therapeutic approach. It can accelerate the decay of the cytosolic Ca(2+) concentration ([Ca(2+)]i) and improve impaired cardiomyocyte relaxation. We hypothesized that this counterintuitive effect is explained by the subcellular arrangement of NCX and local ion gradients within the intracellular Ca(2+) release units. In a parallel model-based and experimental approach, we re-evaluated the location of NCX with regard to the dyadic cleft and its role in modulating [Ca(2+)]i. Stimulated emission depletion imaging revealed NCX in close proximity to junctophilin (the marker for the dyadic cleft). We simulated [Ca(2+)] dynamics in the dyadic cleft considering Ca(2+) channels, NCX molecules and local concentration gradients. Positioning NCX inside the dyadic cleft in our computational model matched its action on spark rate. In forward mode (Ca(2+) out, Na(+) in) NCX decreased spontaneous Ca(2+) release events (spark rate) in simulations and imaging experiments, while in reverse mode it increased them. In paced cardiomyocytes, NCX inhibition consistently increased diastolic [Ca(2+)]. The effects of NCX inhibition on transient amplitude and peak, however, depended on extracellular [Ca(2+)](o) suggesting a role of reverse-mode NCX activity at high [Ca(2+)](o). NCX inhibition prolonged the early rise of [Ca(2+)], corroborating that reverse-mode NCX facilitates the rapid initial increase of [Ca(2+)]i during excitation. Our combined imaging, modelling and functional data support the hypothesis that NCX resides in the dyadic cleft where it bidirectionally shapes Ca(2+) transients and spark activity.
Keywords:	Cardiac Myocytes, Diastolic Dysfunction, Excitation-Contraction Coupling, Na(+)/Ca(2+) Exchanger, Animals, Rats
Source:	Journal of Physiology
ISSN:	0022-3751
Publisher:	Wiley
Date:	7 April 2026
Official Publication:	https://doi.org/10.1113/JP290207
PubMed:	View item in PubMed

Repository Staff Only: item control page

Download Statistics

Downloads

Downloads per month over past year