1. The physiological and pathophysiological roles of the Urocortins Krisztina Kárpáti and Hélène Rivière JPEMS 2015 2015-10-8

2. Content Introduction Physiological roles of the urocortins:  Regulation of stress response  Energy balance and expenditure  Gastrointestinal motility and function  Immune function  Cardiovascular function Pathophysiological roles:  Anxiety  Depression Therapy

3. CRF and CRF-related peptides CRF (1981)  CRFR1  in stress response - PVN of hypothalamus Ucn 1 (1995): - structure similar to CRF - 100-fold higher affinity to CRFR2 - Edinger-Westphal nucleus Ucn 2 and 3 (2001): CRFR2 selective ligands CRF binding protein These petides have different localisations and differents affinity for the receptors different physiological and pathophysiological functions

4. Physiological roles

5. Regulation of the neuroendocrine response to stress Dualism of CRF/Ucn2 and 3 CFR/CRFR1 control the initiation of stress, by the activation of the HPA axis: production of glucocorticoids Increase the blood sugar availability Ucn 2,3/CRFR2 control the recovery from stress, by the inhibition of the HPA axis essential to maintain body and mental health under environmental threating conditions

6. Role on energy balance and expenditure Ucns stimulate the energy expenditure and decrease the food intake. Mediated by brain CRFR2 and mainly by Ucn1 To enhance the energy expenditure Ucn 1 elevate the arterial pressure, body temperature, stimulate the fat utilization and block the effect of orexigen peptides Leptin is an anorexigen peptide which: -contributes to the catabolic functions of the Ucns -provide assistance for the peripheral Ucn 1 to get into the central compartment -stimulate the expression of brain CRFR2

7. Roles on the immune system: the dualistic action of Urocortin 1 Exogenous administration: reduce inflammation - Inhibit cytokines and TNF release -Have palliative effects in experimental models of autoimmune diseases Endogenous Ucn1: pro-inflammatory effect -Ucn1 stimulates IL-1beta and IL-6 secretion by immune cells. -Mediated by CRFR1 -Rheumatoid arthritis, endometriosis, asthma, gastritis, psoriasis, etc CRFR2: protective against CRFR1 deleterious effects ? -the stomach is richer in CRFR2 than in CRFR1, and Ucn1 injection within the stomach seems to repair gastric mucosa from injury.

8. Role on gastrointestinal motility and function Ucns inhibit gastric motility -the gastric emptying is reduced -responsible for the anorectic effects of Ucns? -Mediated by brain CRFR2 (vagal efferents which inhibit gastric contractions) and gut CRFR2 Ucns stimulate colonic motor function - colonic motility, colonic transit time -watery diarrhea -Mediated by CRFR1 Ucns participate in the “irritable bowel syndrome” -painful gastrointestinal stimuli -Nociception is increased by CRFR1 and reduced by CRFR2.

9. Protective and undesired effects on cardiovascular function Inotropic effects: cardiac contractility, heart rate and aortic blood flow Vasodilatory effects via CRFR2. Cardioprotective effect:  in hypoxic stress  in heart failure: -Ucn 1 stimulate the synthesize of Atrial Natriuretic Peptide (ANP) -ANP causes hemodynamic adaptations to heart failure, mediated by CRFR2. Undesired hypertrophic effects: Ucn1 expression is elevated in hypertrophic cardiomyopathy and dilated cardiomyopathy

10. Pathophysiological roles

11. Anxiety CRF  HPA-axis  stress, anxiety CRF deficiency  aberrant stress response In mice: CRFR1 antagonist antalarmin  anxiolisis Ucn 1: - exogenous administration: increased anxiety - endogenous Ucn1: minor importance Ucn 2 and 3: CRFR2: anxiogenesis or no change homeostasis

12. Depression disturbances in HPA axis and aberrant stress coping increased level of CRF in CSF in suicide victims decreased level CRFR1 in suicide victims Ucn 2 and 3: antidepressant-like Ucn 2 or CRFR2 deficiency  depression (altered recovery) Ucn 2 – serotonin level: Administration of Ucn 2  depressive-like behavior Localization-dependant effect

13. Therapeutical possibilities further researches anxiety and depression-like disorders  CRFR1 antagonists obesity: Ucn 1  CRFR2  increased energy expenditure cardioprotective effects: through CRFR2  reduce heart failure GI tract: CRFR2 antagonists  gastric motility increase inflammatory disorders cancer: CRF receprors expression are increased agonists may inhibit proliferaton

14. Acknowledegment Department of Pathophysiology, University of Szeged Zsolt Bagosi M.D., Ph.D. Professor Dr. habil Gyula Szabó, M.D., Ph.D., D.Sc