Urocortin III: stress-recovery & heart-protective hormone

What this is

Urocortin III (Ucn III) is a 38-amino-acid human peptide hormone in the corticotropin-releasing hormone family (CRH, also called CRF) — the same family that contains the hypothalamic peptide which triggers the body's cortisol stress response. Unlike CRH itself, Ucn III binds almost exclusively to one of the family's two receptors, the type 2 CRH receptor (CRHR2), which is the recovery-side arm of the stress axis rather than the activation-side arm. Two groups described the peptide almost simultaneously in 2001 — Lewis and colleagues (PNAS, 2001) named it urocortin III, while Hsu and Hsueh (Nature Medicine, 2001) identified the same molecule from a different starting point and named it stresscopin. Both names refer to the same peptide; "urocortin III" is now the more common usage in the literature, with stresscopin retained as a synonym. The 38-residue stored sequence is the mature peptide; in the human body it is cleaved out of a 161-amino-acid precursor encoded by the UCN3 gene on chromosome 10. Ucn III has no approved therapeutic indication and is used by researchers as a selective probe of CRHR2 biology in stress recovery, mood, cardiovascular function, and pancreatic islet regulation.

History

Urocortin III was discovered in 2001 by two independent teams working from different starting points. Lewis and colleagues at the Salk Institute (PNAS, 2001) mined the public human genome for additional members of the CRH family and identified Ucn III, characterizing its high affinity for CRHR2 alongside much lower affinity for CRHR1 — a selectivity profile that distinguished it from the original CRH and from urocortin I. In parallel, Hsu and Hsueh at Stanford (Nature Medicine, 2001) identified human "stresscopin" and "stresscopin-related peptide" as selective ligands for the type 2 CRH receptor; stresscopin turned out to be the same peptide Lewis named urocortin III, and stresscopin-related peptide corresponds to urocortin II. The two groups interpreted the precursor's processing sites slightly differently, which is why the literature sometimes refers to a 38-residue Ucn III and a 40-residue stresscopin — both originate from the same UCN3 gene. The naming has since stabilized as urocortin III (Ucn III) in most subsequent literature.

What it does

Through CRHR2, Ucn III shifts physiology away from the acute stress response and toward recovery. In rodents, central (intracerebroventricular) administration of Ucn III decreases locomotor activity and increases open-arm exploration on the elevated plus maze — a profile consistent with anxiolytic-like behavior — without the locomotor stimulation seen with CRF1-preferring ligands (Valdez and colleagues, Brain Research, 2003). In the cardiovascular system, CRHR2 is highly expressed in human heart and vasculature, and Ucn III is a potent endothelium-independent vasodilator of isolated human arteries acting via CRHR2 (Wiley and Davenport, British Journal of Pharmacology, 2004); in patients with chronic heart failure, short intravenous infusion increased cardiac index and heart rate and reduced mean arterial pressure and peripheral vascular resistance (Stirrat and colleagues, British Journal of Clinical Pharmacology, 2016). In the pancreas, Ucn III is co-expressed and co-released with insulin from beta cells (Li and colleagues, Endocrinology, 2003) and acts on neighboring delta cells through CRHR2 to potentiate somatostatin secretion, closing a paracrine negative-feedback loop that helps terminate insulin release as blood glucose normalizes (van der Meulen and colleagues, Nature Medicine, 2015).

Mechanism

Ucn III is a selective agonist of CRHR2, a class B (secretin-family) G-protein-coupled receptor. Lewis and colleagues (PNAS, 2001) reported that Ucn III binds CRHR2 with high affinity while showing markedly lower affinity for CRHR1, giving it the cleanest CRHR2 selectivity profile among the natural CRH-family peptides. Hsu and Hsueh (Nature Medicine, 2001) reached the same selectivity conclusion via the stresscopin nomenclature. CRHR2 couples primarily to Gαs, raising intracellular cAMP, and is expressed in brain regions associated with stress recovery (lateral septum, raphe, ventromedial hypothalamus), in heart and vascular smooth muscle, and in pancreatic islet delta cells — the anatomy that grounds the behavioral, cardiovascular, and metabolic phenotypes described above. The pharmacology of this pathway has been dissected with the selective CRHR2 antagonist astressin-2B and with antisauvagine-30, which reverse Ucn III's actions in isolated human artery and islet preparations (Wiley and Davenport, 2004; van der Meulen and colleagues, 2015).

Evidence

• Human: Intravenous Ucn III infusion in patients with chronic heart failure and in age-matched healthy subjects (n = 9 + 7) produced increases in cardiac index and heart rate and reductions in mean arterial pressure and peripheral vascular resistance, of similar magnitude in patients and controls, without reported serious adverse events at the doses tested (Stirrat and colleagues, British Journal of Clinical Pharmacology, 2016). This is the principal published human-physiology study with Ucn III itself; most clinical work in the urocortin family has used the related peptide urocortin 2.
• Animal: Central (intracerebroventricular) Ucn III in rats produced dose-dependent reductions in locomotor activity and an anxiolytic-like profile on the elevated plus maze (Valdez and colleagues, Brain Research, 2003). Subsequent knockout and overexpression studies in mice have implicated Ucn III in stress recovery, social discrimination, and energy homeostasis.
• In vitro / ex vivo: Ucn III bound and activated CRHR2 with high selectivity over CRHR1 in transfected cells (Lewis and colleagues, PNAS, 2001; Hsu and Hsueh, Nature Medicine, 2001). In endothelium-denuded human internal mammary artery preparations, Ucn III reversed endothelin-1-induced constriction by ~61% with potency pD₂ ≈ 8.6, an effect blocked by the CRHR2 antagonist antisauvagine-30 (Wiley and Davenport, British Journal of Pharmacology, 2004). In mouse islets, Ucn III co-released from beta cells stimulated somatostatin secretion from delta cells, closing a negative-feedback loop on insulin (van der Meulen and colleagues, Nature Medicine, 2015).

Known effects

• CRHR2-selective agonism — Established in transfected cells (Lewis and colleagues 2001; Hsu and Hsueh 2001).
• Anxiolytic-like behavior in rodents — Preclinical, after central administration (Valdez and colleagues 2003).
• Vasodilation and increased cardiac output — Demonstrated in isolated human arteries (Wiley and Davenport 2004) and in a short-infusion human physiology study in chronic heart failure (Stirrat and colleagues 2016).
• Paracrine regulation of islet hormone secretion — Established in mouse islets (Li and colleagues 2003; van der Meulen and colleagues 2015). The cellular picture in human islets is partly different: in humans Ucn III is expressed in both alpha and beta cells, whereas in mouse it marks beta cells specifically (Takahashi and colleagues, JCEM, 2004).

Safety signals

No approved indication and no large-scale safety database. The only published human exposure in the references cited here is a short intravenous infusion study in nine heart-failure patients and seven healthy controls (Stirrat and colleagues, 2016), which reported the expected on-target hemodynamic responses (drop in mean arterial pressure, rise in heart rate, warmth and forearm flushing during infusion) without serious adverse events at the doses tested. The peptide's short circulating half-life is the principal practical limitation discussed in the cardiovascular literature for any further therapeutic development.

Regulatory status

• US: Not FDA-approved. Investigational / research-use only.
• EU: Not EMA-approved.
• WADA: Not specifically listed by name; the broader category of peptide hormones and their analogs is governed by S2.

Related peptides

• Urocortin I — the first urocortin identified; binds both CRHR1 and CRHR2 with high affinity, so it is not CRHR2-selective the way Ucn II and Ucn III are.
• Urocortin II — the closer pharmacological neighbor; also CRHR2-selective, with the larger clinical-trial footprint in heart failure.
• Corticotropin-releasing hormone (CRH / CRF) — the founding family member; preferentially activates CRHR1, driving the cortisol-release arm of the stress axis that Ucn III's CRHR2 pathway counter-balances.