Urocortin II: natural stress-recovery & appetite-suppressing hormone

What this is

Stresscopin-related peptide (SRP) is the human form of urocortin II — a 38-amino-acid hormone in the corticotropin-releasing factor (CRF) family. Where CRF itself is the body's "stress alarm" signal, urocortin II works on the opposite half of the system: it binds a different receptor (CRF type 2, or CRHR2) that helps the body recover from stress, rather than ramp it up. In animal studies it reduces food intake and slows gastric emptying without triggering the agitation or hyperactivity that CRF causes (Hsu and Hsueh, Nature Medicine 2001; Reyes and colleagues, PNAS 2001). Researchers are interested in it as a tool for dissecting the two halves of the stress system and as a starting point for cardiovascular drugs — CRHR2 is densely expressed in human heart and blood vessels.

The sequence shown here (IVLSLDVPIGLLQILLEQARARAAREQATTNARILARV, 38 aa) is the mature peptide cleaved from the precursor described by Hsu and Hsueh (2001); the "6-43" naming refers to its position within the predicted precursor protein.

History

Two groups independently identified the peptide in early 2001 by searching public genome databases for sequences related to known CRF-family neuropeptides. Reyes and colleagues (PNAS 2001) cloned the mouse cDNA and named the product urocortin II, characterizing its brain distribution and CRF-R2 selectivity. Hsu and Hsueh (Nature Medicine 2001) identified the human ortholog from the same kind of genomic search and named the two human paralogs stresscopin and stresscopin-related peptide — the framing being that they appeared to mediate stress-coping responses during recovery rather than the initial CRF-driven alarm phase. The International Union of Basic and Clinical Pharmacology subsequently consolidated the naming, with urocortin 2 / SRP and urocortin 3 / stresscopin used interchangeably in the modern literature.

What it does

Urocortin II is a selective agonist of CRHR2, the type 2 CRF receptor (a class B G-protein-coupled receptor). When given centrally in rodents it reduces nighttime food intake and slows gastric emptying, but — unlike CRF acting at CRF-R1 — it does not increase gross motor activity or produce the behavioral signs of arousal (Reyes and colleagues, PNAS 2001; Zorrilla and colleagues, J Pharmacol Exp Ther 2004). This dissociation is the main reason it is used as a research tool: the two CRF receptors split the stress response into an activating arm (CRF-R1) and a recovery/homeostatic arm (CRF-R2).

In the periphery, CRHR2 is densely expressed in human heart and intramyocardial vessels, where urocortin II and urocortin III act as potent vasodilators — in isolated human internal mammary artery, urocortin II produced about 60% maximum relaxation against endothelin-1-induced constriction (Wiley and Davenport, Br J Pharmacol 2004).

Behaviorally, central administration in rats produces only mild motor suppression acutely and a delayed anxiolytic-like effect that emerges hours after dosing rather than immediately — opposite in time-course to the rapid anxiogenic action of CRF at CRF-R1, and the experimental basis for framing CRHR2 signaling as a "compensatory coping" or recovery arm of the stress response (Valdez and colleagues, Brain Research 2002).

Evidence

• Human: Two small acute infusion studies in heart failure patients reported dose-dependent increases in cardiac output and left-ventricular ejection fraction with falls in systemic vascular resistance and cardiac workload (Davis and colleagues, Eur Heart J 2007). The UNICORN Phase II study (Chan and colleagues, JACC: Heart Failure 2013) randomized 53 patients with acute decompensated heart failure to a 4-hour urocortin-2 infusion or placebo; cardiac output rose by 2.1 L/min versus −0.1 L/min on placebo and calculated peripheral resistance fell by about 47%, with transient flushing in 55% of urocortin-2 recipients and no treatment-related serious adverse events. Beyond cardiovascular research, no approved therapeutic indication exists.
• Animal: Central administration in rodents suppresses food intake, delays gastric emptying, and reduces heat-induced edema (Hsu and Hsueh, Nature Medicine 2001); attenuates nighttime feeding without inducing motor activation (Reyes and colleagues, PNAS 2001).
• In vitro: Mouse urocortin II binds CRF-R2 with Ki ≈ 0.66 nM and CRF-R1 with Ki > 100 nM — a >150-fold selectivity for CRHR2; EC50 for cAMP accumulation at CRF-R2 ≈ 0.14 nM (Reyes and colleagues, PNAS 2001). In human cardiac membranes, CRHR2 displays a KD of about 0.21 nM (Wiley and Davenport, Br J Pharmacol 2004).

Known effects

• Selective CRHR2 activation — pharmacological hallmark; the defining property and reason for its use as a research probe (Reyes and colleagues, PNAS 2001).
• Vasodilation in human vasculature — preclinical (ex vivo human tissue) and early clinical infusion data; relaxes endothelin-1-constricted human internal mammary artery (Wiley and Davenport, Br J Pharmacol 2004).
• Cardiac output augmentation in heart failure — Phase II, small studies; raises CO and LVEF without reflex tachycardia (Davis and colleagues, Eur Heart J 2007; Chan and colleagues, JACC: Heart Failure 2013).
• Anorexigenic / appetite-suppressing in animals — preclinical only; mechanism dissociated from CRF-R1-driven arousal (Hsu and Hsueh, Nature Medicine 2001; Zorrilla and colleagues, J Pharmacol Exp Ther 2004).
• Delayed gastric emptying in animals — preclinical only (Hsu and Hsueh, Nature Medicine 2001; Million and colleagues, Am J Physiol Gastrointest Liver Physiol 2002).
• Mild locomotor suppression and delayed anxiolytic-like effect — preclinical only (Valdez and colleagues, Brain Research 2002).

Safety signals

Published human data are limited to short investigational infusions in heart failure cohorts. In the UNICORN study (Chan and colleagues, JACC: Heart Failure 2013), the most common acute effect was transient flushing (55% on urocortin-2 vs 23% on placebo). Blood pressure fell — by design, given the vasodilator action — by roughly 16 mm Hg systolic versus placebo, with concurrent transient declines in renal indices. No treatment-related serious adverse events were reported in that 4-hour, 53-patient study. No chronic-exposure human safety data are published.

Regulatory status

• US: Not FDA-approved for any indication. Research/investigational use only.
• EU: Not EMA-approved.
• WADA: Not specifically listed by name on the WADA Prohibited List; no approved therapeutic use exists for it as a CRHR2 agonist.

Related peptides

• Urocortin 1 — the original urocortin; binds both CRF-R1 and CRF-R2 (non-selective), in contrast to urocortin II's CRHR2 selectivity.
• Urocortin III / stresscopin — the other CRHR2-selective human ligand identified in the same Hsu and Hsueh (2001) study; closely related biology.
• Corticotropin-releasing factor (CRF/CRH) — the founding family member; binds CRF-R1 preferentially and drives the activating arm of the stress response that urocortin II's receptor counterbalances.