Small open reading frames pack a big punch in cardiac calcium regulation

Abstract

Cardiac contraction requires continuous cycles of calcium release and reuptake between the sarcoplasm and sarcoplasmic reticulum. In vertebrate cardiomyocytes, re-sequestration of calcium to the sarcoplasmic reticulum is accomplished by the SERCA whose activity is dampened by interaction with the small integral membrane proteins, phospholamban and sarcolipin. In a recent report published in Science, Magny et al identify 2 small peptides in Drosophila encoded in a putative long noncoding RNA that buffers calcium reuptake by sarco/endoplasmic reticulum Ca²⁺-ATPase 2a in a similar manner to sarco/endoplasmic reticulum Ca²⁺-ATPase 2a regulation by phospholamban and sarcolipin. These findings demonstrate that regulation of Ca²⁺-ATPases by small transmembrane peptides is a conserved and ancient strategy. Furthermore, this study highlights the possibility that there may be many undiscovered small peptides encoded within putative long non-coding RNAs that regulate important biological pathways.

Figure. Calcium cycling in cardiomyocytes

Activation of the L-type channel by an action potential allows calcium to enter the sarcoplasm where it triggers opening of the ryanodine receptor (RyR). Calcium then escapes its storage site in the SR lumen and binds to sarcomeres to activate muscle contraction. Following contraction, the sarcoplasmic calcium is recycled back to the SR by SERCA in vertebrates and Ca-P60A in invertebrates. The small peptides sarcolamban A and B are derived from a single gene and dampen Ca-P60A activity in a manner similar to PLN and SLN acting upon SERCA.