Background: Enterochromaffin (EC) cells of the diffuse neuroendocrine cell system secrete serotonin (5-HT) with activation of gut motility, secretion and pain. These cells express adenosine (ADORA) receptors and are considered to function as mechano-sensors. Physiological pathways mediating mechano-sensitivity and adenosine responsiveness remain to be fully elucidated, as are their roles in inflammatory bowel disease (IBD) and neoplasia. Methods and Results: Pure (98-99%) FACS-sorted normal and IBD human EC cells and neoplastic EC cells (KRJ-I) were studied. IBD-EC cells and KRJ-I over-expressed ADORA2B. NECA, a general ADORA receptor agonist, stimulated, while the A2B receptor antagonist MRS1754 inhibited, 5-HT release (EC50=1.8x10-6M; IC50=3.7x10-8M) which was associated with corresponding alterations in intracellular cAMP levels and pCREB(Ser133). Mechanical stimulation using a rhythmic flex model induced transcription and activation of Tph1 (tryptophan hydroxylase) and VMAT1 (vesicular monoamine transporter 1) and the release of 5-HT, which could be inhibited by MRS1754 and amplified by NECA. Secretion was also inhibited by H-89 (PKA inhibitor) while Tph1 and VMAT1 transcription was regulated by PKA/MAPK and PI3K-mediated signaling. Normal and IBD-EC cells also responded to NECA and mechanical stimulation with PKA activation, cAMP production and 5-HT release, effects reversible by MRS1754. Conclusion: EC cells express stimulatory ADORA2B and rhythmic stretch induces A2B activation, PKA/MAPK/IP3-dependent transcription, and PKA-dependent secretion of 5-HT synthesis and secretion. Receptor expression is amplified in IBD and neoplasia and 5-HT release is increased. Determination of factors that regulate EC cell function are necessary for understanding its role as a mechanosensory cell and to facilitate the development of agents that can selectively target cell function in EC cell-associated disease.
- Crohn's disease
- enterochromaffin cell
- Copyright © 2011, American Journal of Physiology- Gastrointestinal and Liver Physiology