Human pheochromocytomas express orexin receptor type 2 gene and display an in vitro secretory response to orexins A and B.
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.
Mazzocchi
G
G
Department of Human Anatomy and Physiology, Section of Anatomy, University of Padua, Via Gabelli 65, I-35121 Padua, Italy. mazzocch@ux1.unipd.it
Malendowicz
L K
LK
Aragona
F
F
Rebuffat
P
P
Gottardo
L
L
Nussdorfer
G G
GG
D000310:Adrenal Gland Neoplasms / Q000378:metabolism*; D002352:Carrier Proteins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004963:Estrenes / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides / Q000494:pharmacology*; D064446:Orexin Receptors; D000068797:Orexins; D010673:Pheochromocytoma / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010738:Type C Phospholipases / Q000502:physiology
D002352:Carrier Proteins; D004963:Estrenes; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011760:Pyrrolidinones; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D011493:Protein Kinase C; D010738:Type C Phospholipases