Work

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

Year: 2016

Type: article

Abstract: The sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) and phospholamban (PLN) complex regulates heart relaxation through its removal of cytosolic Ca 2+ 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 d <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.

Source: Journal of Biological Chemistry

DOI: 10.1074/jbc.m116.738807

Authors: Kailey J. Soller, Jing Yang, Gianluigi Veglia, Michael T. Bowser

Institution: University of Minnesota

Language: English

Topic: Cardiac electrophysiology and arrhythmias

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,430