Glucagon‑like peptide‑1 analogue exendin‑4 modulates serotonin transporter expression in intestinal epithelial cells

Cui,Xiufang; Zhao,Xiaojing; Wang,Ying; Yang,Yan; Zhang,Hongjie

doi:10.3892/mmr.2020.10976

Glucagon‑like peptide‑1 analogue exendin‑4 modulates serotonin transporter expression in intestinal epithelial cells

Authors:
- Xiufang Cui
- Xiaojing Zhao
- Ying Wang
- Yan Yang
- Hongjie Zhang
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Affiliations: Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: February 6, 2020 https://doi.org/10.3892/mmr.2020.10976
Pages: 1934-1940
Copyright: © Cui et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Serotonin‑selective reuptake transporter (SERT) regulates extracellular availability of serotonin (5‑hydroxytryptamine; 5‑HT) and participates in the pathogenesis of functional disorders. Colonic SERT expression is decreased in colonic sensitized rats, and the glucagon‑like peptide‑1 analogue, exendin‑4, reduces visceral hypersensitivity by decreasing 5‑HT levels and increasing SERT expression. The present in vitro study aimed to further investigate the effects of exendin‑4 on SERT expression, and to examine the role of GLP‑1 and its receptor in the regulation of 5‑HT. SERT mRNA and protein expression levels were detected by reverse transcription‑quantitative PCR and western blotting. A [3H]‑5‑HT reuptake experiment was performed in IEC‑6 rat intestinal epithelial cells treated with exendin‑4. Effects on the adenosine cyclophosphate (AC)/PKA pathway were examined by variously treating cells with the AC activator forskolin, the protein kinase A (PKA) inhibitor H89 and the AC inhibitor SQ22536. Exendin‑4 treatment upregulated SERT expression and enhanced 5‑HT reuptake in IEC‑6 cells. Also, PKA activity in IEC‑6 cells was increased by both exendin‑4 and forskolin, whereas these effects were abolished by the pre‑treatment of exendin‑9, which is a GLP‑1R inhibitor, SQ22536 and H89. In conclusion, exendin‑4 may be associated with the upregulation of SERT expression via the AC/PKA signaling pathway.

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1	Gwee KA, Gonlachanvit S, Ghoshal UC, Chua ASB, Miwa H, Wu J, Bak YT, Lee OY, Lu CL, Park H, et al: Second Asian consensus on irritable bowel syndrome. J Neurogastroenterol Motil. 25:343–362. 2019. View Article : Google Scholar : PubMed/NCBI
2	Quigley EM, Abdel-Hamid H, Barbara G, Bhatia SJ, Boeckxstaens G, De Giorgio R, Delvaux M, Drossman DA, Foxx-Orenstein AE, Guarner F, et al: A global perspective on irritable bowel syndrome: A consensus statement of the world gastroenterology organisation summit task force on irritable bowel syndrome. J Clin Gastroenterol. 46:356–366. 2012. View Article : Google Scholar : PubMed/NCBI
3	Kanazawa M, Hongo M and Fukudo S: Visceral hypersensitivity in irritable bowel syndrome. J Gastroenterol Hepatol. 26 (Suppl 3):S119–S121. 2011. View Article : Google Scholar
4	Carrasco-Labra A, Lytvyn L, Falck-Ytter Y, Surawicz CM and Chey WD: AGA technical review on the evaluation of functional diarrhea and diarrhea-predominant irritable bowel syndrome in adults (IBS-D). Gastroenterology. 157:859–880. 2019. View Article : Google Scholar : PubMed/NCBI
5	Hellström PM, Hein J, Bytzer P, Björnssön E, Kristensen J and Schambye H: Clinical trial: The glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome: A randomized, placebo-controlled, double-blind study. Aliment Pharmacol Ther. 29:198–206. 2009. View Article : Google Scholar : PubMed/NCBI
6	Nozu T, Miyagishi S, Kumei S, Nozu R, Takakusaki K and Okumura T: Glucagon-like peptide-1 analog, liraglutide, improves visceral sensation and gut permeability in rats. J Gastroenterol Hepatol. 33:232–239. 2018. View Article : Google Scholar : PubMed/NCBI
7	Smith NK, Hackett TA, Galli A and Flynn CR: GLP-1: Molecular mechanisms and outcomes of a complex signaling system. Neurochem Int. 128:94–105. 2019. View Article : Google Scholar : PubMed/NCBI
8	Hellström PM: GLP-1 playing the role of a gut regulatory compound. Acta Physiol (Oxf). 201:151–156. 2011. View Article : Google Scholar : PubMed/NCBI
9	Smits MM, Tonneijck L, Muskiet MH, Kramer MH, Cahen DL and van Raalte DH: Gastrointestinal actions of glucagon-like peptide-1-based therapies: Glycaemic control beyond the pancreas. Diabetes Obes Metab. 18:224–235. 2016. View Article : Google Scholar : PubMed/NCBI
10	Yang Y, Cui X, Chen Y, Wang Y, Li X, Lin L and Zhang H: Exendin-4, an analogue of glucagon-like peptide-1, attenuates hyperalgesia through serotonergic pathways in rats with neonatal colonic sensitivity. J Physiol Pharmacol. 65:349–357. 2014.PubMed/NCBI
11	Hellström PM, Smithson A, Stowell G, Greene S, Kenny E, Damico C, Leone-Bay A, Baughman R, Grant M and Richardson P: Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat. Regul Pept. 179:71–76. 2012. View Article : Google Scholar : PubMed/NCBI
12	Wei Y and Mojsov S: Distribution of GLP-1 and PACAP receptors in human tissues. Acta Physiol Scand. 157:355–357. 1996. View Article : Google Scholar : PubMed/NCBI
13	Xiao YF, Nikolskaya A, Jaye DA and Sigg DC: Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway. Cardiovasc Diabetol. 10:62011. View Article : Google Scholar : PubMed/NCBI
14	Morikawa O, Sakai N, Obara H and Saito N: Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol. 349:317–324. 1998. View Article : Google Scholar : PubMed/NCBI
15	Rumajogee P, Madeira A, Vergé D, Hamon M and Miquel MC: Up-regulation of the neuronal serotoninergic phenotype in vitro: BDNF and cAMP share Trk B-dependent mechanisms. J Neurochem. 83:1525–1528. 2002. View Article : Google Scholar : PubMed/NCBI
16	Kerckhoffs AP, ter Linde JJ, Akkermans LM and Samsom M: SERT and TPH-1 mRNA expression are reduced in irritable bowel syndrome patients regardless of visceral sensitivity state in large intestine. Am J Physiol Gastrointest Liver Physiol. 302:G1053–G1060. 2012. View Article : Google Scholar : PubMed/NCBI
17	El-Salhy M, Wendelbo I and Gundersen D: Serotonin and serotonin transporter in the rectum of patients with irritable bowel disease. Mol Med Rep. 8:451–455. 2013. View Article : Google Scholar : PubMed/NCBI
18	Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD and Gershon MD: Localization and function of a 5-HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci. 16:2352–2364. 1996. View Article : Google Scholar : PubMed/NCBI
19	Miwa J, Echizen H, Matsueda K and Umeda N: Patients with constipation-predominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrhea-predominant patients and subjects with normal bowel habits. Digestion. 63:188–194. 2001. View Article : Google Scholar : PubMed/NCBI
20	Bertrand PP and Bertrand RL: Serotonin release and uptake in the gastrointestinal tract. Auton Neurosci. 153:47–57. 2010. View Article : Google Scholar : PubMed/NCBI
21	Grundy D: 5-HT system in the gut: Roles in the regulation of visceral sensitivity and motor functions. Eur Rev Med Pharmacol Sci. 12 (Suppl 1):S63–S67. 2008.
22	Salaga M, Binienda A, Tichkule RB, Thakur GA, Makriyannis A, Storr M and Fichna J: The novel peripherally active cannabinoid type 1 and serotonin type 3 receptor agonist AM9405 inhibits gastrointestinal motility and reduces abdominal pain in mouse models mimicking irritable bowel syndrome. Eur J Pharmacol. 836:34–43. 2018. View Article : Google Scholar : PubMed/NCBI
23	Chen Y, Li Z, Yang Y, Lin L and Zhang H: Role of glucagon-like peptide-1 in the pathogenesis of experimental irritable bowel syndrome rat models. Int J Mol Med. 31:607–613. 2013. View Article : Google Scholar : PubMed/NCBI
24	Liu Z, Zhang M, Zhou T, Shen Q and Qin X: Exendin-4 promotes the vascular smooth muscle cell re-differentiation through AMPK/SIRT1/FOXO3a signaling pathways. Atherosclerosis. 276:58–66. 2018. View Article : Google Scholar : PubMed/NCBI
25	Franzellitti S and Fabbri E: Cyclic-AMP mediated regulation of ABCB mRNA expression in mussel haemocytes. PLoS One. 8:e616342013. View Article : Google Scholar : PubMed/NCBI
26	Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, Fujimoto EK, Goeke NM, Olson BJ and Klenk DC: Measurement of protein using bicinchoninic acid. Anal Biochem. 150:76–85. 1985. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
28	Camilleri M: Serotonergic modulation of visceral sensation: Lower gut. Gut. 51 (Suppl 1):i81–i86. 2002. View Article : Google Scholar : PubMed/NCBI
29	Matheus N, Mendoza C, Iceta R, Mesonero JE and Alcalde AI: Melatonin inhibits serotonin transporter activity in intestinal epithelial cells. J Pineal Res. 48:332–339. 2010. View Article : Google Scholar : PubMed/NCBI
30	Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, Crowell MD, Sharkey KA, Gershon MD, Mawe GM and Moses PL: Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology. 126:1657–1664. 2004. View Article : Google Scholar : PubMed/NCBI
31	Gill RK, Anbazhagan AN, Esmaili A, Kumar A, Nazir S, Malakooti J, Alrefai WA and Saksena S: Epidermal growth factor upregulates serotonin transporter in human intestinal epithelial cells via transcriptional mechanisms. Am J Physiol Gastrointest Liver Physiol. 300:G627–G636. 2011. View Article : Google Scholar : PubMed/NCBI
32	Ramamoorthy S, Cool DR, Mahesh VB, Leibach FH, Melikian HE, Blakely RD and Ganapathy V: Regulation of the human serotonin transporter. Cholera toxin-induced stimulation of serotonin uptake in human placental choriocarcinoma cells is accompanied by increased serotonin transporter mRNA levels and serotonin transporter-specific ligand binding. J Biol Chem. 268:21626–21631. 1993.PubMed/NCBI
33	Cui XF, Zhou WM, Yang Y, Zhou J, Li XL, Lin L and Zhang HJ: Epidermal growth factor upregulates serotonin transporter and its association with visceral hypersensitivity in irritable bowel syndrome. World J Gastroenterol. 20:13521–13529. 2014. View Article : Google Scholar : PubMed/NCBI