Research ArticleCalcium signaling

Widespread control of calcium signaling by a family of SERCA-inhibiting micropeptides

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Science Signaling  06 Dec 2016:
Vol. 9, Issue 457, pp. ra119
DOI: 10.1126/scisignal.aaj1460

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Inhibiting SERCA in more tissues

Calcium triggers critical signaling events in all cell types. The membrane transporter SERCA moves calcium from the cytoplasm into the sarcoplasmic or endoplasmic reticulum to keep the basal cytoplasmic concentration of calcium low. Micropeptides that inhibit SERCA have been characterized in muscle. However, SERCA isoforms are found in all tissues, leading Anderson et al. to search for micropeptides that could perform this inhibitory function in nonmuscle tissues. They discovered two such micropeptides, endoregulin (ELN) and another-regulin (ALN) which inhibit the activity of SERCA isoforms that are abundant in nonmuscle tissues. These results raise the possibility that other membrane transporters related to SERCA could also be regulated by micropeptides.


Micropeptides function as master regulators of calcium-dependent signaling in muscle. Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), the membrane pump that promotes muscle relaxation by taking up Ca2+ into the sarcoplasmic reticulum, is directly inhibited by three muscle-specific micropeptides: myoregulin (MLN), phospholamban (PLN), and sarcolipin (SLN). The widespread and essential function of SERCA across diverse cell types has raised questions as to how SERCA is regulated in cells that lack MLN, PLN, and SLN. We identified two transmembrane micropeptides, endoregulin (ELN) and another-regulin (ALN), that share key amino acids with their muscle-specific counterparts and function as direct inhibitors of SERCA pump activity. The distribution of transcripts encoding ELN and ALN mirrored that of SERCA isoform-encoding transcripts in nonmuscle cell types. Our findings identify additional members of the SERCA-inhibitory micropeptide family, revealing a conserved mechanism for the control of intracellular Ca2+ dynamics in both muscle and nonmuscle cell types.

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