Human Endothelin-1 (ET-1) is a 21-residue bicyclic vasoactive peptide that activates ETA and ETB endothelin receptors. Its molecular architecture is stabilized by two intramolecular disulfide bonds, Cys1-Cys15 and Cys3-Cys11, followed by a hydrophobic C-terminal segment ending in Trp21.

ET-1 provides a well-defined ligand for studies of vascular smooth-muscle contraction, endothelial signaling, receptor subtype pharmacology, inflammatory remodeling and peptide–GPCR structural recognition.

Product Information

A Bicyclic 21-Residue Peptide

Endothelin-1 differs structurally from many short, flexible inflammatory peptides. Four cysteine residues form two intramolecular disulfide bridges, producing a constrained N-terminal and central architecture while leaving the extreme C-terminal region available for deep receptor-pocket engagement.

The C-terminal residues Asp18-Ile19-Ile20-Trp21 are particularly important in endothelin receptor recognition. Structural studies show that this segment inserts deeply into the orthosteric binding pocket, with Trp21 forming extensive interactions within the receptor core.

ETA and ETB Are Pharmacologically Distinct Receptor Systems

ET-1 can activate both major endothelin receptor subtypes, but ETA and ETB should not be treated as functionally interchangeable.

ETA receptors are strongly associated with vascular smooth-muscle contraction and sustained pressor signaling. ETB receptors occur in several cellular contexts, including vascular endothelium, where activation can promote nitric oxide and prostacyclin release, as well as other tissues where ETB signaling can produce different responses.

We recommend documenting receptor subtype and cellular background when comparing ET-1 potency or functional responses.

Different Receptor Desensitization Kinetics

ETA and ETB receptors also differ in the way signaling declines after agonist exposure. Experimental studies of human receptor subtypes found relatively sustained ETA signaling, whereas ETB underwent much faster agonist-dependent inactivation and phosphorylation.

This makes ET-1 useful for investigating how the same peptide ligand can produce different temporal signaling profiles through related GPCR subtypes.

Endothelin-1 at the Vascular–Inflammatory Interface

ET-1 is best known for its strong vasoactive properties, but its experimental relevance extends beyond acute contraction. Endothelin signaling has been investigated in vascular remodeling, fibroblast responses, endothelial dysfunction and inflammatory tissue environments.

For pain and inflammation research, ET-1 is therefore particularly useful as a neurovascular and tissue-remodeling mediator rather than as a conventional nociceptive peptide equivalent to Bradykinin.

Disulfide Architecture and Structure–Activity Relationships

The two disulfide bridges help stabilize the characteristic endothelin fold. However, receptor subtype recognition is not determined by disulfide geometry alone. Studies using linearized and truncated analogs have demonstrated a major contribution from the C-terminal receptor-binding region.

This makes ET-1 a useful scaffold for dissecting the relative contributions of peptide folding, receptor-pocket insertion and subtype-specific ligand recognition.

Analytical Considerations

Correct oxidative folding should be considered part of ET-1 identity. A peptide containing the correct 21-residue sequence but an incorrect disulfide connectivity is not structurally equivalent to native ET-1.

The sequence also contains Met7, making oxidation of methionine another relevant LC-MS consideration during synthesis, storage and prolonged handling.

For receptor or structure–activity studies, our Peptide Quality Control capabilities support analytical HPLC and mass spectrometry according to the selected specification.

Research Applications

Human ET-1 can support ETA/ETB receptor pharmacology, calcium and phosphoinositide signaling studies, vascular smooth-muscle experiments, endothelial biology, receptor desensitization research, fibrosis models and endothelin peptide SAR.

Researchers working with related neurovascular mediators can explore our Pain and Inflammation Modulation Peptides collection.

Endothelin fragments, residue substitutions and receptor-directed analogs can be evaluated through Chemical Peptide Synthesis.

Frequently Asked Questions

How many disulfide bonds are present in human Endothelin-1?

Two intramolecular disulfide bonds are present: Cys1-Cys15 and Cys3-Cys11.

Does ET-1 activate both ETA and ETB receptors?

Yes. ET-1 is an agonist at both receptor subtypes, although receptor distribution, signaling kinetics and downstream physiological responses differ.

Why is Trp21 important?

The C-terminal Trp21 inserts into the endothelin receptor binding pocket and participates in key interactions involved in high-affinity ligand recognition.

Can linear or disulfide-modified ET-1 analogs be synthesized?

Defined cysteine substitutions, truncated peptides and other endothelin analogs can be evaluated through Chemical Peptide Synthesis.

Research Use Only.