Phospholamban (PLN), the reversible inhibitor of the sarco(endo)plasmic 
reticulum Ca(2+)-ATPase (SERCA2a), is a key regulator of myocyte Ca(2+) cycling 
with a significant role in heart failure. We previously showed that the single 
amino acid difference between human and mouse PLN results in increased 
inhibition of Ca(2+) cycling and cardiac remodeling and attenuated stress 
responses in transgenic mice expressing the human PLN (hPLN) in the null 
background. Here we dissect the molecular and electrophysiological processes 
triggered by the superinhibitory hPLN in the mouse. Using a multidisciplinary 
approach, we performed global gene expression analysis, electrophysiology, and 
mathematical simulations on hPLN mice. We identified significant changes in a 
series of Na(+) and K(+) homeostasis genes/proteins (including Kcnd2, Scn9a, 
Slc8a1) and ionic conductance (including L-type Ca(2+) current, Na(+)/Ca(2+) 
exchanger, transient outward K(+) current). Simulation analysis suggests that 
this electrical remodeling has a critical role in rescuing cardiac function by 
improving sarcoplasmic reticulum Ca(2+) load and overall Ca(2+) dynamics. 
Furthermore, multiple structural and transcription factor gene expression 
changes indicate an ongoing structural remodeling process, favoring hypertrophy 
and myogenesis while suppressing apoptosis and progression to heart failure. Our 
findings expand current understanding of the hPLN function and provide 
additional insights into the downstream implications of SERCA2a superinhibition 
in the mammalian heart.