Abstract
// Wenxue Zhang 1, 2, 3, 4 , Dongyan Zhao 5 , Qingqing Qi 1, 2 , Xin Long 1, 2 , Yueyue Li 1, 2 , Peng Wang 1, 2 , Yanbo Yu 1, 2 , Lixiang Li 1, 2 , Yiyuan Sun 1, 2 , Zhen Li 1, 2 , Yanqing Li 1, 2 and Xiuli Zuo 1, 2 1 Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China 2 Laboratory of Translational Gastroenterology, Qilu Hospital, Shandong University, Jinan 250012, China 3 Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China 4 Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China 5 Department of Gastroenterology, General Hospital of Puyang Oilfield, Puyang 457000, China Correspondence to: Xiuli Zuo, email: zuoxiuli@sina.com Keywords: NMDARs; NR2B; proBDNF; visceral hypersensitivity; diarrhea-predominant irritable bowel syndrome Received: December 01, 2016 Accepted: January 02, 2018 Published: January 02, 2018 ABSTRACT Colonic mucosal N-methyl-D-aspartate receptors (NMDARs) contribute to visceral hypersensitivity in diarrhea-predominant irritable bowel syndrome (IBS-D) by increasing the production of brain-derived neurotrophic factor (BDNF). We investigated which of the multiple NMDAR subtypes and BDNF isoforms are responsible for this effect. Immunohistochemistry and Western blotting were used to detect levels of colonic mucosal NR2A-D subunits and the precursor (proBDNF) and mature (mBDNF) forms of BDNF in 67 participants. Only NR2B subunit expression was elevated in the colonic mucosa of IBS-D patients, in parallel with increased total BDNF and proBDNF expression. Expression of 15 kDa mBDNF was not detected in the colonic mucosa. NR2B, total BDNF and proBDNF levels correlated with abdominal pain scores. Quantitative real-time PCR and Western blotting showed that NMDAR activation substantially induced total BDNF/proBDNF expression in HT-29 cells, while the NMDAR inhibitor MK-801 and the NR2B subunit antagonist Ro25-6981 each completely blocked these effects. Thus, colonic mucosal NR2B-containing NMDARs may contribute to visceral hypersensitivity in IBS-D patients by upregulating BDNF, especially proBDNF.
Highlights
Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder, and involves abdominal pain, discomfort or bloating associated with changes in bowel habits [1]
NR2B subunit expression was elevated in the colonic mucosa of irritable bowel syndrome (IBS-D) patients, in parallel with increased total brain-derived neurotrophic factor (BDNF) and precursor of BDNF (proBDNF) expression
Previous studies in three kinds of research subjects have demonstrated that the activation of colonic mucosal N-methyl-D-aspartate receptors (NMDARs) contributes to the visceral hypersensitivity in IBS by increasing the production of BDNF [9, 28]
Summary
Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder, and involves abdominal pain, discomfort or bloating associated with changes in bowel habits [1]. In the Rome III criteria, four subtypes of IBS are described: diarrhea-predominant IBS (IBS-D), IBS with constipation, mixed-type IBS, and unsubtyped IBS. Among these subtypes, the diarrhea subtype especially impairs patients’ quality of life by limiting their diet and their ability to travel or eat out [4]. Visceral hypersensitivity has been recognized as a crucial mechanism in IBS-D [5]. The variety of subunit combinations results in a large number of NMDAR subtypes, and the NR2 (A-D) subunits are major determinants of the functional heterogeneity of the receptors [8]. Previous studies have demonstrated that mucosal NMDARs in the colon contribute to the visceral www.impactjournals.com/oncotarget s456
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