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Human Pheochromocytomas Express Orexin Receptor Type 2 Gene and Display an in Vitro Secretory Response to Orexins A and B

Departments of Human Anatomy and Physiology, Section of Anatomy (G.M., L.K.M., P.R., L.G., G.G.N.), and Urology (F.A.), University of Padua, I-35121 Padua, Italy

Address all correspondence and requests for reprints to: Prof. G. Mazzocchi, Department of Human Anatomy and Physiology, Section of Anatomy, Via Gabelli 65, I-35121 Padova, Italy. E-mail: mazzocch{at}ux1.unipd.it

Abstract

Orexins A and B are hypothalamic peptides, that act through two receptor subtypes, called OX1-R and OX2-R. OX1-R selectively binds orexin A, whereas OX2-R is nonselective for both orexins. High levels of OX1-R mRNA and low levels of OX2-R mRNA have been previously detected in the human adrenal cortex and medulla. Here we demonstrated by RT-PCR the expression of the OX2-R, but not the OX1-R, gene in 10 benign secreting pheochromocytomas. Both orexins A and B stimulated catecholamine secretion from pheochromocytoma slices; the maximal effective concentration was 10^-8 mol/liter. Orexins A and B (10^-8 mol/liter) increased IP3, but not cAMP production, by tumor slices, and the effect was blocked by the PLC inhibitor U-73122. The catecholamine response to 10^-8 mol/liter orexins A and B was abolished by either U-73122 or the PKC antagonist calphostin C and was unaffected by the adenylate cyclase inhibitor SQ-22536 and the PKA inhibitor H-89. Collectively, these findings suggest that orexins stimulate catecholamine secretion from human pheochromocytomas, acting through OX2-R coupled to the PLC-PKC signaling pathway.

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