Urocortin II (mouse): stress & heart-protective brain peptide

What this is

Urocortin II is a 38-amino-acid neuropeptide first cloned from mouse brain in 2001. It belongs to the corticotropin-releasing factor (CRF) family — the same family as CRF itself, urocortin I, and urocortin III — but unlike CRF it binds selectively to the type-2 CRF receptor (CRHR2) and does not appreciably activate the type-1 receptor (Reyes et al., PNAS 2001). The card stores the mouse sequence; the human ortholog was independently identified the same year and named "stresscopin-related peptide" before the urocortin nomenclature was harmonized (Hsu & Hsueh, Nature Medicine 2001). Because CRHR2 is concentrated in the heart, vasculature, skeletal muscle, and discrete brain stress circuits, urocortin II has been studied as a probe for those tissues and as a candidate therapeutic for heart failure.

History

Urocortin II was discovered by data-mining the then-new human genome draft for sequences homologous to CRF. Reyes and colleagues at the Salk Institute identified a candidate region, used homologous primers to clone the mouse cDNA, and characterized the predicted 38-residue mature peptide as a selective CRHR2 ligand (Reyes et al., PNAS 2001). A second new family member, urocortin III, was reported by the same lab a few months later, also with high affinity for CRHR2 (Lewis et al., PNAS 2001). In parallel, Hsu and Hsueh independently cloned the human orthologs from a genomic database search and proposed the names "stresscopin-related peptide" (the human equivalent of urocortin II) and "stresscopin" (urocortin III), highlighting their selective binding to the type-2 CRH receptor (Hsu & Hsueh, Nature Medicine 2001). The urocortin nomenclature is the one that stuck.

A decade later, a triple-knockout mouse lacking urocortin I, urocortin II, and urocortin III was generated to test whether the urocortins are truly redundant; the knockouts revealed an essential role for the urocortins in adaptive recovery from stress rather than in the acute stress response itself (Neufeld-Cohen et al., PNAS 2010).

What it does

Through CRHR2, urocortin II produces three reproducible effects in animal and early human studies:

• Cardiovascular: Acts as an arterial vasodilator and a positive inotrope. Intra-arterial infusion in healthy volunteers produced prolonged forearm vasodilatation, partly dependent on endothelial nitric oxide and cytochrome-P450 metabolites of arachidonic acid (Venkatasubramanian et al., Journal of the American Heart Association 2013). In patients with chronic heart failure, intravenous infusion produced dose-dependent increases in cardiac output and left-ventricular ejection fraction with falls in systemic vascular resistance (Davis et al., European Heart Journal 2007).
• Feeding: Systemic urocortin II suppresses food intake in mice via CRHR2 without producing conditioned taste aversion, diarrhea, or other malaise-like signs that complicate urocortin I and CRF — making it the cleaner CRF-family anorexigenic probe (Fekete et al., British Journal of Pharmacology 2011).
• Stress and anxiety circuits: Genetic loss of all three urocortins impairs stress recovery rather than the acute stress response, supporting a role in returning HPA-axis and behavioral state to baseline after a stressor (Neufeld-Cohen et al., PNAS 2010).

Evidence

• Human: A small dose-escalation infusion study in eight men with stable systolic heart failure reported dose-dependent increases in cardiac output (up to ~+2 L/min) and LVEF (up to ~+14 %) with falls in systemic vascular resistance and no significant neurohormonal activation (Davis et al., European Heart Journal 2007). An intra-arterial study in 18 healthy male volunteers established that urocortin-2 evokes potent, prolonged forearm arterial vasodilatation, with the response partly dependent on endothelial nitric oxide and arachidonic-acid-derived cytochrome-P450 metabolites (Venkatasubramanian et al., Journal of the American Heart Association 2013). The UNICORN study — a double-blind randomized placebo-controlled trial of 53 patients with acute decompensated heart failure — found that a 4-hour urocortin-2 infusion increased cardiac output by ~2 L/min relative to placebo, reduced calculated peripheral resistance by ~47 %, and produced significant 24-hour falls in B-type natriuretic peptide, without treatment-related serious adverse events (Chan et al., JACC: Heart Failure 2013). These are early-phase mechanistic and pilot studies, not pivotal trials.
• Animal: Mouse and rat work established CRHR2-selective binding and characterized the cardiovascular, feeding, and stress-recovery phenotypes summarized above (Reyes et al., PNAS 2001; Fekete et al., British Journal of Pharmacology 2011; Neufeld-Cohen et al., PNAS 2010).
• In vitro: Receptor-binding and cAMP-accumulation assays in the original cloning paper showed selective activation of CRHR2 with essentially no activity on CRHR1 (Reyes et al., PNAS 2001).

Known effects

• Arterial vasodilation and positive inotropy — Phase I / small mechanistic human infusion studies (Davis et al. 2007; Venkatasubramanian et al. 2013).
• Augmented cardiac output in acute decompensated heart failure — Small randomized placebo-controlled trial (UNICORN; Chan et al. 2013).
• Appetite suppression without aversive side effects — Preclinical, rodent (Fekete et al. 2011).
• Stress-recovery facilitation — Inferred from triple-knockout phenotype, not from agonist administration (Neufeld-Cohen et al. 2010).
• CRHR2-selective agonism — In vitro, cloned-receptor assays (Reyes et al. 2001).

Safety signals

Published human exposure is limited to small short-duration infusion studies in healthy volunteers and in heart-failure patients. Reported effects align with the pharmacology — falls in blood pressure and systemic vascular resistance, with modest changes in heart rate — and no treatment-related serious adverse events were reported in the small cohorts studied (Davis et al., European Heart Journal 2007; Venkatasubramanian et al., Journal of the American Heart Association 2013; Chan et al., JACC: Heart Failure 2013). The total human exposure remains too small to characterize long-term or population-level safety.

Regulatory status

• US: Not FDA-approved for any indication. Investigational; human use is restricted to clinical research.
• EU: Not EMA-approved.
• WADA: Not specifically listed by name on the WADA Prohibited List; the broader status of CRF-family peptides on the list has not been independently confirmed for urocortin II.

Related peptides

• Urocortin I — the original member of the urocortin sub-family; binds both CRHR1 and CRHR2, so its biology overlaps with CRF in a way urocortin II's does not.
• Urocortin III (stresscopin) — the third family member, also CRHR2-selective, identified shortly after urocortin II (Lewis et al., PNAS 2001; Hsu & Hsueh, Nature Medicine 2001).
• Corticotropin-releasing factor (CRF / CRH) — the founding family member; binds CRHR1 preferentially and drives the acute HPA-axis stress response that the urocortins are thought to modulate and resolve.