The physiological and pathophysiological roles of

the Urocortins Krisztina Kárpáti and Hélène Rivière

JPEMS 20152015-10-8

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

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

Physiological roles

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

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

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.

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.

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

Pathophysiological roles

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

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

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

Acknowledegment

Department of Pathophysiology, University of Szeged

• Zsolt Bagosi M.D., Ph.D.• Professor Dr. habil Gyula Szabó, M.D., Ph.D., D.Sc