PI3K p110α/Akt Signaling Negatively Regulates Secretion of the Intestinal Peptide Neurotensin Through Interference of Granule Transport

Neurotensin (NT), an intestinal peptide secreted from N cells in the small bowel, regulates a variety of physiological functions of the gastrointestinal tract, including secretion, gut motility, and intestinal growth. The class IA phosphatidylinositol 3-kinase (PI3K) family, which comprised of p110 catalytic (alpha, beta and delta) and p85 regulatory subunits, has been implicated in the regulation of hormone secretion from endocrine cells. However, the underlying mechanisms remain poorly understood. In particular, the role of PI3K in intestinal peptide secretion is not known. Here, we show that PI3K catalytic subunit, p110 alpha, negatively regulates NT secretion in vitro and in vivo. We demonstrate that inhibition of p110 alpha, but not p110 beta, induces NT release in BON, a human endocrine cell line, which expresses NT mRNA and produces NT peptide in a manner analogous to N cells, and QGP-1, a pancreatic endocrine cell line that produces NT peptide. In contrast, overexpression of p110 alpha decreases NT secretion. Consistently, p110 alpha-inhibition increases plasma NT levels in mice. To further delineate the mechanisms contributing to this effect, we demonstrate that inhibition of p110 alpha increases NT granule trafficking by up-regulating alpha-tubulin acetylation; NT secretion is prevented by overexpression of HDAC6, an alpha-tubulin deacetylase. Moreover, ras-related protein Rab27A (a small G protein) and kinase D-interacting substrate of 220 kDa (Kidins220), which are associated with NT granules, play a negative and positive role, respectively, in p110 alpha-inhibition-induced NT secretion. Our findings identify the critical role and novel mechanisms for the PI3K signaling pathway in the control of intestinal hormone granule transport and release. (Molecular Endocrinology 26: 1380-1393, 2012)