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