Reversal of Phospholamban Inhibition of the Sarco(endo)plasmic Reticulum Ca2+-ATPase (SERCA) Using Short, Protein-interacting RNAs and Oligonucleotide Analogs.

The sarco(endo)plasmic reticulum Ca-ATPase (SERCA) and phospholamban (PLN) complex regulates heart relaxation through its removal of cytosolic Ca during diastole. Dysfunction of this complex has been related to many heart disorders and is therefore a key pharmacological target. There are currently no therapeutics that directly target either SERCA or PLN. It has been previously reported that single-stranded DNA binds PLN with strong affinity and relieves inhibition of SERCA in a length-dependent manner. In the current article, we demonstrate that RNAs and single-stranded oligonucleotide analogs, or xeno nucleic acids (XNAs), also bind PLN strongly (K <10 nm) and relieve inhibition of SERCA. Affinity for PLN is sequence-independent. Relief of PLN inhibition is length-dependent, allowing SERCA activity to be restored incrementally. The improved in vivo stability of XNAs offers more realistic pharmacological potential than DNA or RNA. We also found that microRNAs (miRNAs) 1 and 21 bind PLN strongly and relieve PLN inhibition of SERCA to a greater extent than a similar length random sequence RNA mixture. This may suggest that miR-1 and miR-21 have evolved to contain distinct sequence elements that are more effective at relieving PLN inhibition than random sequences.