Rheostatic Regulation of the SERCA/Phospholamban Membrane Protein Complex Using Non-Coding RNA and Single-Stranded DNA oligonucleotides Journal Article

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Authors: Soller, K. J.; Verardi, R.; Jing, M.; Abrol, N.; Yang, J; Walsh, N.; Vostrikov, V. V.; Robia, S. L.; Bowser, M. T.; Veglia, G
Article Title: Rheostatic Regulation of the SERCA/Phospholamban Membrane Protein Complex Using Non-Coding RNA and Single-Stranded DNA oligonucleotides
Abstract: The membrane protein complex between sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) and phospholamban (PLN) is a prime therapeutic target for reversing cardiac contractile dysfunctions caused by calcium mishandling. So far, however, efforts to develop drugs specific for this protein complex have failed. Here, we show that non-coding RNAs and single-stranded DNAs (ssDNAs) interact with and regulate the function of the SERCA/PLN complex in a tunable manner. Both in HEK cells expressing the SERCA/PLN complex, as well as in cardiac sarcoplasmic reticulum preparations, these short oligonucleotides bind and reverse PLN's inhibitory effects on SERCA, increasing the ATPase's apparent Ca(2+) affinity. Solid-state NMR experiments revealed that ssDNA interacts with PLN specifically, shifting the conformational equilibrium of the SERCA/PLN complex from an inhibitory to a non-inhibitory state. Importantly, we achieved rheostatic control of SERCA function by modulating the length of ssDNAs. Since restoration of Ca(2+) flux to physiological levels represents a viable therapeutic avenue for cardiomyopathies, our results suggest that oligonucleotide-based drugs could be used to fine-tune SERCA function to counterbalance the extent of the pathological insults.
Journal Title: Scientific reports
Volume: 5
ISSN: 2045-2322; 2045-2322
Publisher: Unknown  
Journal Place: England
Date Published: 2015
Start Page: 13000
Language: eng
DOI/URL:

10.1038/srep13000
Notes: LR: 20150902; GR: GM063533/GM/NIGMS NIH HHS/United States; GR: GM064742/GM/NIGMS NIH HHS/United States; GR: GM072701/GM/NIGMS NIH HHS/United States; JID: 101563288; OID: NLM: PMC4543939; 2015/03/04 [received]; 2015/06/26 [accepted]; epublish