Linkage of s100a10 (p11) to enteric 5-HT4-mediated serotonergic signaling roles in GI motility, enteric nervous system development, and co-morbid dysfunction of gut and brain

Project Narrative Signaling molecules, such as serotonin (5-HT), which do not cross cell membranes, must activate receptors on cell surfaces to which receptors are transported from their intracellular site of biosynthesis. Evidence suggests that insertion of the 5-HT4 receptor subtype into cell surface membranes in the brain is critically dependent on an interaction with another molecule, p11, which functions as an adaptor. We plan to test three hypotheses strongly supported by our preliminary data, (i) that the p11-5-HT4 interaction is necessary for insertion of 5-HT4 receptors into cell surface membranes of intestinal nerve and epithelial cells, is thus (ii) essential for 5- HT4-stimulation of enteric neuronal development and function, and, (iii) when defective, underlies the frequent co-existence of 5-HT4-mediated brain and gut disorders, including constipation and depression.