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Acta Physiologica 2009; Volume 197, Supplement 675
Joint meeting of The Slovenian Physiological Society, The Austrian Physiological Society and The Federation of European Physiological Societies
11/12/2009-11/15/2009
Ljubljana, Slovenia
FUNCTIONAL CONSEQUENCES OF VASOPRESSIN AND CORTICOLIBERIN RECEPTORS CO-EXPRESSION IN NATIVE AND HETEROLOGOUS MODELS
Abstract number: L122
Murat1 B, Devost2 D, Andres1 M, Corbani1 M, Zingg2 H, Manning3 M, Guillon1 G
1Institut de Gnomique Fonctionnelle, Montpellier, France
2McGill University, Dept. Pharmacology and Therapeuthics Montreal, Qubec, Canada.
3University of Toledo, College of Medecine, Toledo, OH, USA
In mammals, Vasopressin (VP) and corticoliberin (CRF) co-regulate ACTH and insulin release by acting in synergism at the pituitary and pancreas levels respectively. Using a new selective fluorescent V1b analogue and a selective anti-CRHR1 antibody, we demonstrate that such synergism implies V1b and CRHR1 receptors co-localization. Yet, the molecular mechanisms involved remain partially unknown.
We first extended the VP and CRF synergism to the bovine adrenal chromaffin gland. We showed that VP and CRF both stimulate catecholamines secretion and also act in synergism. Such potentiation may be related to modifications of second messenger cascade. Thus, we observed a clear potentiation of VP-stimulated Inositol Phosphates (IPs) accumulation by CRF and a weak but significant effect of VP on CRF-stimulated cAMP production.
To go further in these mechanisms, we transfected HEK293 cells with functional tagged V1b and CRHR1 receptors. We first demonstrated by BRET and co-immunoprecipitation experiments that these 2 receptors heterodimerized in living cells. Then, we explored the potential modifications of V1b and CRHR1 receptors pharmacology upon receptor co-transfection. We found that CRF might alter VP binding at high doses. More interestingly, we showed that VP potentiated the CRF-stimulated cAMP accumulation. This effect was dose- dependent, receptor-mediated and partially due to PKC activation. Yet, 25% of this potentiation effect was insensitive to a full PLC antagonist suggesting another mechanism of synergy. CRF may also significantly potentiate VP-stimulated IPs accumulation.
In conclusion, we show that VP/CRF potentiation seems to be a general phenomenon in native tissues. We also bring evidence that, beside second messengers crosstalk, heterodimerization of V1b/CRHR1 receptors may also be involved in such a phenomenom.
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Acta Physiologica 2009; Volume 197, Supplement 675 :L122