Elabela (ELA / Apela / Toddler)

Overview

Elabela (ELA), also known as Apela or Toddler, is the second endogenous peptide ligand of the APJ receptor (APLNR), identified independently in 2013-2014 by three research groups studying different aspects of its biology. Chng and colleagues at ASTAR Singapore identified it as "Elabela" through comparative genomics of a previously unannotated open reading frame. Pauli and colleagues at the Schier laboratory at Harvard identified the same peptide as "Toddler," a motility factor driving mesodermal cell migration in zebrafish gastrulation. Multiple subsequent groups termed the peptide "Apela" (Apelin Receptor Early Endogenous Ligand).

The discovery of Elabela established that the APJ receptor, like several other GPCRs, has more than one endogenous ligand. While apelin and Elabela both activate APJ, they have distinct expression patterns, developmental roles, and pharmacological profiles. Elabela is the first peptide ligand to act at APJ during embryonic development: APJ-null and Elabela-null mice both have cardiovascular defects, whereas apelin knockouts have milder phenotypes, revealing the developmental primacy of Elabela signaling in some contexts.

The Elabela gene had been previously annotated as "non-coding" in many genome assemblies due to its small size and unusual genomic structure. Its characterization as a bona fide peptide-encoding gene has become a frequently cited example of how bioinformatic reannotation can reveal overlooked peptide hormones — a theme shared with phoenixin and spexin.

Structure/Sequence

Human Mature Elabela (ELA-32): QRPVNLTMRRKLRKHNCLQRRCMPLHSRVPFP-OH

• Length: 32 amino acids
• Molecular weight: ~3,900 g/mol
• Gene: APELA (APLN early endogenous ligand; also called ELA, chromosome 4q32.3)
• Processing: Preproprotein processed to ELA-32, ELA-21, and ELA-11 mature forms
• Shorter forms: ELA-21 and ELA-11 retain receptor binding activity; ELA-11 corresponds to the C-terminal 11 residues
• Internal disulfide: Cys14-Cys23 forms an intramolecular disulfide bond
• C-terminal proline: Analogous to apelin's C-terminal proline, though apelin's key residue is the terminal phenylalanine

Relationship to Apelin

Despite sharing the APJ receptor, Elabela has no sequence similarity to apelin. The two peptides represent an example of convergent evolution at the same receptor — or, more likely, recruitment of two different ligand families to a common GPCR during vertebrate evolution.

Species Conservation

Elabela is conserved across vertebrates, with clear orthologs in zebrafish, Xenopus, chicken, and mammals. The C-terminal region shows the highest conservation.

Mechanism of Action

APJ Receptor Activation

Elabela binds and activates the APJ receptor:

• Gi/o coupling
• PI3K/Akt activation
• MAPK/ERK activation
• β-arrestin recruitment
• Partial cross-desensitization with apelin

Elabela and apelin may bind APJ through partially overlapping but distinct interfaces, and the two ligands can show biased agonism — preferentially coupling to different downstream effectors.

Developmental Roles

• Mesoderm migration: In zebrafish, Elabela (Toddler) promotes migratory behavior of mesendodermal cells during gastrulation
• Cardiovascular development: Elabela is essential for heart tube formation and vascular patterning
• Embryonic APJ signaling: Elabela is the dominant APJ ligand during early development, preceding apelin expression temporally
• Primitive streak formation: Role in germ layer formation

Cardiovascular Function

• Positive inotropy (like apelin)
• Vasodilation
• Blood pressure reduction
• Anti-fibrotic effects
• Protective in pressure overload models

Kidney

• Elabela expression is high in kidney
• Modulates fluid balance
• Anti-fibrotic effects in kidney disease models
• Preeclampsia research: plasma Elabela reduced in preeclampsia

Cardiac Regeneration

• Role in zebrafish cardiac regeneration
• Potential for promoting cardiomyocyte proliferation and survival

Relationship to Preeclampsia

Elabela knockout mice develop preeclampsia-like phenotype (hypertension in pregnancy, proteinuria), and supplementation with Elabela rescues the phenotype. This has made Elabela of interest in placental and hypertensive disorder research.

Research Summary

Common Discussion Topics

1. Second ligand discovery — The identification of Elabela as a second APJ ligand illustrated that deorphanized receptors can have multiple endogenous peptide agonists. This theme recurs in GPCR biology: ghrelin and cortistatin both bind GHS-R1a; angiotensin II derivatives bind multiple AT receptors.

2. Non-coding to coding reannotation — Elabela's gene had been annotated as "non-coding" in many reference genomes due to its small size. Its reannotation reinforced the idea that the peptidome contains overlooked small ORFs (smORFs) encoding bioactive peptides. Similar examples include phoenixin and spexin.

3. Developmental primacy — During early embryogenesis, Elabela is the primary APJ ligand, preceding apelin expression. This sequential ligand deployment at a common receptor is a recurring theme in developmental signaling.

4. Preeclampsia link — The phenotype of Elabela-null mice mirrors key features of human preeclampsia, including hypertension and proteinuria in pregnancy. Reduced Elabela in human preeclampsia samples suggests the axis may be translationally relevant.

5. Dual ligand pharmacology — The availability of two ligands for APJ creates opportunities for biased agonism and ligand-specific drug design. Selective agonists favoring Elabela-like or apelin-like signaling modes are active areas of research.

Related Compounds

• Apelin — first APJ receptor endogenous ligand
• Angiotensin II — related peptide at paralogous AT1 receptor
• Angiotensin-(1-7) — counterregulatory RAS peptide with shared ACE2 processing