Functional CRF receptors in BON cells stimulate serotonin release.
BON cells are human, pancreatic carcinoid-derived, endocrine-like cells that share functional similarities with intestinal enterochromaffin (EC) cells. We investigated the presence of corticotropin-releasing factor (CRF) receptors, their signalling pathways and the functional effects of their stimulation in BON cells (clone #7). Expression analysis showed that BON cells contain mRNA for the CRF receptor types 1 and 2 (CRF1/2), although CRF2 mRNA levels were 23-fold higher than those of CRF1 mRNA. The CRF1/2 ligand, rat/human (r/h)CRF (EC50 = 233 nM), and the selective CRF2 ligand, human urocortin 3 (Ucn 3) (EC50 = 48 nM), induced a dose-dependent increase in cAMP formation. Effects of r/hCRF were blocked by 44% with the selective CRF1 antagonist DMP-696, while the selective CRF2 antagonist antisauvagine-30 had only marginal effects. Both ligands (100 nM) stimulated the release of serotonin with similar efficacy (3-fold increase over basal). Effects of r/hCRF, but not Ucn 3, were blocked by pre-incubation with antisauvagine-30. These observations demonstrate that the EC cell-related BON cells express functional CRF2 receptors linked to the release of serotonin. This suggests that EC cells may be a target for CRF and/or Ucn 3 in the intestine during stress-related responses. Actions of CRF/Ucn 3 and EC cell-derived mediators, such as serotonin, might underlie several motor, secretory and/or sensory disorders of the gastrointestinal (GI) tract which may play a role in the pathophysiology of functional GI disorders, such as irritable bowel syndrome.
von Mentzer
Bengt
B
Department of Molecular Pharmacology, AstraZeneca R&D Mölndal, SE-43183 Mölndal, Sweden. Bengt.Mentzer@astrazeneca.com
Murata
Yousuke
Y
Ahlstedt
Ingela
I
Lindström
Erik
E
Martínez
Vicente
V
D045744:Cell Line, Tumor; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004759:Enterochromaffin Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D010446:Peptide Fragments / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D054832:Urocortins
C404928:DMP 696; D010446:Peptide Fragments; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; C426704:UCN3 protein, human; D054832:Urocortins; C116607:antisauvagine 30; D012701:Serotonin; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP