PI3K p110α/Akt Signaling Negatively Regulates Secretion of the Intestinal Peptide Neurotensin Through Interference of Granule Transport
PI3K p110α/Akt Signaling Negatively Regulates Secretion of the Intestinal Peptide Neurotensin Through Interference of Granule Transport
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DOI：
10.1210/me.2012-1024
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发表时间：
2012-08-01
影响因子：
--
通讯作者：
Evers, B. Mark
中科院分区：
文献类型：
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作者：
Li, Jing;Song, Jun;Evers, B. Mark
神经降压素（NT）是一种由小肠N细胞分泌的肠肽，调节胃肠道的多种生理功能，包括分泌、肠道运动和肠道生长。IA类磷脂酰肌醇3-激酶（PI 3 K）家族包括p110催化亚基（α、β和δ）和p85调节亚基，其参与调节内分泌细胞的激素分泌。然而，对潜在的机制仍然知之甚少。具体而言，PI 3 K在肠肽分泌中的作用尚不清楚。在这里，我们表明，PI 3 K催化亚基，p110 α，负调节NT分泌在体外和体内。我们证明，抑制p110 α，但不是p110 β，诱导NT释放在BON，人内分泌细胞系，表达NT mRNA，并产生NT肽的方式类似于N细胞，和QGP-1，胰腺内分泌细胞系，产生NT肽。相反，p110 α过表达减少NT分泌。因此，p110 α抑制可增加小鼠血浆NT水平。为了进一步阐明这种作用的机制，我们证明了抑制p110 α通过上调α-微管蛋白乙酰化增加NT颗粒运输; NT分泌通过HDAC 6（一种α-微管蛋白脱乙酰酶）的过度表达而被阻止。此外，ras相关蛋白Rab 27 A（一种小G蛋白）和220 kDa激酶D相互作用底物（Kidins 220），它们与NT颗粒相关，分别在p110 α抑制诱导的NT分泌中起负性和正性作用。我们的研究结果确定了PI 3 K信号通路在控制肠道激素颗粒转运和释放中的关键作用和新机制。（分子内分泌学26：1380-1393，2012）
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)