Key result
Loss of phospholamban phosphorylation blunts adrenergic Ca2+ transient amplitude and SR Ca2+ load.
Why the study?
Previous studies using transgenic overexpression of non-phosphorylatable PLB showed partially preserved Ca2+ release and inotropy during adrenergic stimulation, but were potentially confounded by transgene insertion and compensatory mechanisms.
A novel CRISPR/Cas9 mouse model reveals that phospholamban phosphorylation is strictly required for a complete cellular adrenergic response, demonstrating that previous observations of preserved inotropy in transgenic models were likely driven by compensatory adaptations rather than preserved physiological function.
Impaired adrenergic Ca2+ handling in PLB-DM mice challenges prior transgenic models; leaves open relevance to human HF therapy.
Adrenergic stimulation modulates excitation-contraction coupling (ECC) and cardiac function primarily through protein kinase A (PKA), which phosphorylates multiple ECC proteins. Key PKA targets include phospholamban (PLB), a critical regulator of SERCA2-mediated Ca 2+ uptake. Previous studies using transgenic overexpression of non-phosphorylatable PLB reported that Ca 2+ release and inotropy were partially preserved in response to adrenergic stimulation; however, this model may be confounded by transgene insertion and other compensatory mechanisms. To address these limitations, we used CRISPR/Cas9 to generate a mouse model with genomic mutations resulting in non-phosphorylatable substitutions at relevant residues in PLB (PLB-S16A/T17A, PLB-DM). Mass spectrometry confirmed the complete absence of PLB phosphorylation in PLB-DM hearts. PLB-DM mice displayed normal heart structure, mild bradycardia and reduced cardiac output. PLB-DM myocytes showed reduced Ca 2+ transient amplitude and decay, and reduced SR Ca 2+ load compared to WT controls under adrenergic stimulation. L-type Ca 2+ current density and kinetics remained unaltered in PLB-DM myocytes, suggesting that previous reports of preserved inotropy likely reflected model-specific compensatory adaptations. These results suggest that PLB phosphorylation is required to achieve a complete cellular adrenergic response.
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Gowda et al. (2026) studied None (Basic science mouse model). PLB-S16A/T17A genomic mutation (PLB-DM) vs. Wild-type (WT) C57Bl/6J mice was evaluated on Ca2+ transient amplitude and sarcoplasmic reticulum (SR) Ca2+ load under adrenergic stimulation. Loss of phospholamban phosphorylation blunted the Ca2+ handling component of the adrenergic response, reducing Ca2+ transient amplitude and SR Ca2+ load compared to wild-type controls.
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