Depressed Ca-handling in cardiomyocytes is frequently attributed to impaired 
sarcoplasmic reticulum (SR) function in human and experimental heart failure. 
Phospholamban (PLN) is a key regulator of SR and cardiac function, and PLN 
mutations in humans have been associated with dilated cardiomyopathy (DCM). We 
previously reported the deletion of the highly conserved amino acid residue 
arginine 14 (nucleic acids 39, 40 and 41) in DCM patients. This basic amino acid 
is important in maintaining the upstream consensus sequence for PKA 
phosphorylation of Ser 16 in PLN. To assess the function of this mutant PLN, we 
introduced the PLN-R14Del in cardiac myocytes of the PLN null mouse. Transgenic 
lines expressing mutant PLN-R14Del at similar protein levels to wild types 
exhibited no inhibition of the initial rates of oxalate-facilitated SR Ca uptake 
compared to PLN-knockouts (PLN-KO). The contractile parameters and Ca-kinetics 
also remained highly stimulated in PLN-R14Del cardiomyocytes, similar to PLN-KO, 
and isoproterenol did not further stimulate these hyper-contractile basal 
parameters. Consistent with the lack of inhibition on SR Ca-transport and 
contractility, confocal microscopy indicated that the PLN-R14Del failed to 
co-localize with SERCA2a. Moreover, PLN-R14Del did not co-immunoprecipitate with 
SERCA2a (as did WT-PLN), but rather co-immunoprecipitated with the sarcolemmal 
Na/K-ATPase (NKA) and stimulated NKA activity. In addition, studies in HEK cells 
indicated significant fluorescence resonance energy transfer between 
PLN-R14Del-YFP and NKAα1-CFP, but not with the NKA regulator phospholemman. 
Despite the enhanced cardiac function in PLN-R14Del hearts (as in 
PLN-knockouts), there was cardiac hypertrophy (unlike PLN-KO) coupled with 
activation of Akt and the MAPK pathways. Thus, human PLN-R14Del is misrouted to 
the sarcolemma, in the absence of endogenous PLN, and alters NKA activity, 
leading to cardiac remodeling.