Activation of (Na+ + K+)-ATPase modulates cardiac L-type Ca2+ channel function
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Updated: Jun 24, 2026
Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
Dong I Lee1, Michael G Klein, Weizhong Zhu
1Department of Biochemistry, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Abstract:
Cellular Ca(2+) signaling underlies diverse vital biological processes, including muscle contractility, memory encoding, fertilization, cell survival, and cell death. Despite extensive studies, the fundamental control mechanisms that regulate intracellular Ca(2+) movement remain enigmatic. We have found recently that activation of the (Na(+)+K(+))-ATPase markedly potentiates intracellular Ca(2+) transients and contractility of rat heart cells. Little is known about the pathway responsible for the activation of the (Na(+)+K(+))-ATPase-initiated Ca(2+) signaling. Here, we demonstrate a novel mechanism in which activation of the (Na(+)+K(+))-ATPase is coupled to increased L-type Ca(2+) channel function through a signaling cascade involving Src and ERK1/2 but not well established regulators of the channel, such as adrenergic receptor system or activation of PKA or CaMKII. We have also identified Ser(1928), a phosphorylation site for the alpha1 subunit of the L-type Ca(2+) channel that may participate in the activation of the (Na(+)+K(+))-ATPase-mediated Ca(2+) signaling. The findings reported here uncover a novel molecular cross-talk between activation of the (Na(+)+K(+))-ATPase and L-type Ca(2+) channel and provide new insights into Ca(2+) signaling mechanisms for deeper understanding of the nature of cellular Ca(2+) handling in heart.
Insights
Activation of the sodium-potassium pump enhances heart cell calcium signaling via a novel pathway involving Src and ERK1/2. This study reveals new insights into cellular calcium handling and L-type calcium channel regulation.
Area of Science:
- Cardiovascular Physiology
- Cellular Signaling
- Molecular Biology
Background:
- Cellular calcium (Ca2+) signaling is crucial for numerous physiological processes, including heart function.
- Mechanisms regulating intracellular Ca2+ transients and cardiac contractility are not fully understood.
- The role of the (Na+)+K(+))-ATPase in modulating cardiac Ca2+ signaling remains largely unexplored.
Purpose of the Study:
- To elucidate the signaling pathway linking (Na+)+K(+))-ATPase activation to enhanced cardiac Ca2+ transients.
- To identify the molecular players involved in (Na+)+K(+))-ATPase-mediated potentiation of Ca2+ signaling.
- To investigate the cross-talk between (Na+)+K(+))-ATPase and L-type Ca2+ channels in heart cells.
Main Methods:
- Utilized rat heart cells to study cellular Ca2+ signaling.
- Investigated the involvement of Src and ERK1/2 in the signaling cascade.
- Examined the phosphorylation status of the L-type Ca2+ channel alpha1 subunit, specifically Ser1928.
Main Results:
- Demonstrated that (Na+)+K(+))-ATPase activation potentiates intracellular Ca2+ transients and contractility in rat heart cells.
- Identified a novel signaling cascade involving Src and ERK1/2 that couples (Na+)+K(+))-ATPase activation to L-type Ca2+ channel function.
- Found that this pathway is independent of established regulators like adrenergic receptors, PKA, or CaMKII.
- Identified Ser1928 on the L-type Ca2+ channel alpha1 subunit as a potential phosphorylation site involved in this signaling.
Conclusions:
- Uncovered a novel mechanism of molecular cross-talk between (Na+)+K(+))-ATPase activation and L-type Ca2+ channel function.
- Provided new insights into the regulation of cellular Ca2+ handling in the heart.
- Highlighted the significance of the Src/ERK1/2 pathway and Ser1928 phosphorylation in cardiac Ca2+ signaling modulation.
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