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http://dx.doi.org/10.5352/JLS.2021.31.7.662

Mirtazapine Regulates Pacemaker Potentials of Interstitial Cells of Cajal in Murine Small Intestine  

Kim, Byung Joo (Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University)
Publication Information
Journal of Life Science / v.31, no.7, 2021 , pp. 662-670 More about this Journal
Abstract
Interstitial cells of Cajal (ICCs) are the pacemaking cells in the gastrointestinal (GI) muscles that generate the rhythmic oscillation in membrane potentials known as slow waves. In the present study, we investigated the effects of mirtazapine, a noradrenergic and serotonergic antidepressant, on pacemaking potential in cultured ICCs from the murine small intestine. The whole-cell patch-clamp configuration was used to record pacemaker potential in cultured ICCs. Mirtazapine induced pacemaker potential depolarizations in a concentration-dependent manner in the current clamp mode. Y25130 (a 5-HT3 receptor antagonist), RS39604 (a 5-HT4 receptor antagonist), and SB269970 (a 5-HT7 receptor antagonist) had no effects on mirtazapine-induced pacemaker potential depolarizations. Also, methoctramine, a muscarinic M2 receptor antagonist, had no effect on mirtazapine-induced pacemaker potential depolarizations, whereas 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a muscarinic M3 receptor antagonist, inhibited the depolarizations. When guanosine 5'-[β-thio] diphosphate (GDP-β-S; 1 mM) was in the pipette solution, mirtazapine-induced pacemaker potential depolarization was blocked. When an external Ca2+ free solution or thapsigargin, a Ca2+-ATPase inhibitor of the endoplasmic reticulum, was applied, the generation of pacemaker potentials disappeared, and under these conditions, mirtazapine induced pacemaker potential depolarizations. In addition, protein kinase C (PKC) inhibitor, calphostin C, and chelerythrine inhibited mirtazapine-induced pacemaker potential depolarizations. These results suggest that mirtazapine regulates pacemaker potentials through muscarinic M3 receptor activation via a G protein-dependent and an external or internal Ca2+-independent PKC pathway in the ICCs. Therefore, mirtazapine can control GI motility through ICCs.
Keywords
Gastrointestinal tract; interstitial cells of Cajal; mirtazapine; motility; pacemaker potentials;
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1 Sung, T. S., Jeon, J. P., Kim, B. J., Hong, C., Kim, S. Y., Kim, J., Jeon, J. H., Kim, H. J., Suh, C. K., Kim, S. J. and So, I. 2011. Molecular determinants of PKA-dependent inhibition of TRPC5 channel. Am. J. Physiol. Cell Physiol. 301, C823-C832.   DOI
2 Thomas, S. G. 2000. Irritable bowel syndrome and mirtazapine. Am. J. Psychiatry 157, 1341-1342.   DOI
3 Hirst, G. D. S., Garcia-Londono, A. P. and Edwards, F. R. 2006. Propagation of slow waves in the Guinea-pig gastric antrum. J. Physiol. 571, 165-177.   DOI
4 Jung, H. Y., Lee, S. I., Kim, D. H. and Choi, E. J. 2004. A case of restless leg syndrome induced by mirtazapine in a patient with major depressive disorder. Clin. Psychopharmacol. Neurosci. 15, 488-491.
5 Huizinga, J. D., Chang, G., Diamant, N. E. and El-Sharkawy, T. Y. 1984. Electrophysiological basis of excitation of canine colonic circular muscle by cholinergic agents and substance P. J. Pharmacol. Exp. Ther. 231, 692-699.
6 Huizinga, J. D., Thuneberg, L., Kluppel, M. and Malysz, H. B. 1995. The W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 373, 347-349.   DOI
7 Inoue, R. and Chen, S. 1993. Physiology of muscarinic receptor-operated nonselective cation channels in guinea-pig ileal smooth muscle. EXS. 66, 261-268.
8 Kim, B. J., Lim, H. H., Yang, D. K., Jun, J. Y., Chang, I. Y., Park, C. S., So, I., Stanfield, P. R. and Kim, K. W. 2005. Melastatin-type transient receptor potential channel 7 is required for intestinal pacemaking activity. Gastroenterology 129, 1504-1517.   DOI
9 Kim, S. W., Shin, I. S., Kim, J. M., Kang, H. C., Mun, J. U., Yang, S. J. and Yoon, J. S. 2006. Mirtazapine for severe gastroparesis unresponsive to conventional prokinetic treatment. Psychosomatics 47, 440-442.   DOI
10 Koh, S. D., Sanders, K. M. and Ward, S. M. 1998. Spontaneous electrical rhythmicity in cultured interstitial cells of Cajal from the murine small intestine. J. Physiol. 513, 203-213.   DOI
11 Huizinga, J. D. and Faussone-Pellegrini, M. S. 2005. About the presence of interstitial cells of Cajal outside the musculature of the gastrointestinal tract. J. Cell. Mol. Med. 9, 468-473.   DOI
12 Epperson, A., Hatton, W. J., Callaghan, B., Doherty, P., Walker, R. L., Sanders, K. M., Ward, S. M. and Horowitz, B. 2000. Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal. Am. J. Physiol. Cell Physiol. 279, C529-C539.   DOI
13 Gooden, J. Y. and Takahashi, P. Y. 2013. Mirtazapine treatment of diabetic gastroparesis as a novel method to reduce tube-feed residual: a case report. J. Med. Case Rep. 7, 38.   DOI
14 Hanani, M., Farrugia, G. and Komuro, T. 2005. Intercellular coupling of interstitial cells of Cajal in the digestive tract. Int. Rev. Cytol. 242, 249-282.
15 Timmer, C. J., Sitsen, J. M. and Delbressine, L. P. 2000. Clinical pharmacokinetics of mirtazapine. Clin. Pharmacokinet. 38, 461-474.   DOI
16 Yin, J., Wang, W., Winston, J. H., Zhang, R. and Chen, J. D. 2010. Ameliorating effects of mirtazapine on visceral hypersensitivity in rats with neonatal colon sensitivity. Neurogastroenterol. Motil. 22, 1022-1028.   DOI
17 Zhu, M. H., Kim, T. W., Ro, S., Yan, W., Ward, S. M., Koh, S. D. and Sanders, K. M. 2009. A Ca2+-activated Cl-conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. J. Physiol. 587, 4905-4918.   DOI
18 Koh, S. D., Ward, S. M., Ordog, T., Sanders, K. M. and Horowitz, B. 2003. Conductances responsible for slow wave generation and propagation in interstitial cells of Cajal. Curr. Opin. Pharmacol. 3, 579-582.   DOI
19 Fawcett, J. and Barkin, R. L. 1998. Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. J. Affect. Disord. 51, 267-285.   DOI
20 Halpert, A., Dalton, C. B., Diamant, N. E., Toner, B. B., Hu, Y., Morris, C. B., Bangdiwala, S. I., Whitehead, W. E. and Drossman, D. A. 2005. Clinical response to tricyclic antidepressants in functional bowel disorders is not related to dosage. Am. J. Gastroenterol. 100, 664-671.   DOI
21 O'Grady, G., Wang, T. H. H., Du, P., Angeli, T., Lammers, W. J. and Cheng, L. K. 2014. Recent progress in gastric arrhythmia: Pathophysiology, clinical significance and future horizons. Clin. Exp. Pharmacol. Physiol. 41, 854-862.   DOI
22 Yin, J., Song, J., Lei, Y., Xu, X. and Chen, J. D. Z. 2014. Prokinetic effects of mirtazapine on gastrointestinal transit. Am. J. Physiol. Gastrointest. Liver Physiol. 306, G796-G801.   DOI
23 Lang, R. J., Tonta, M. A., Zoltkowski, B. Z., Meeker, W. F., Wendt, I. and Parkington, H. C. 2006. Pyeloureteric peristalsis: Role of atypical smooth muscle cells and interstitial cells of Cajal-like cells as pacemakers. J. Physiol. 576, 695-705.   DOI
24 Lee, K. P., Jun, J. Y., Chang, I. Y., Suh, S. H., So, I. and Kim, K. W. 2005. TRPC4 is an essential component of the nonselective cation channel activated by muscarinic stimulation in mouse visceral smooth muscle cells. Mol. Cells 20, 435-441.
25 Liu, H. N., Ohya, S., Nishizawa, Y., Sawamura, K., Iino, S., Syed, M. M., Goto, K., Imaizumi, Y. and Nakayama, S. 2011. Serotonin augments gut pacemaker activity via 5-HT3 receptors. PLoS One 6, e24928.   DOI
26 Ogata, R., Inoue, Y., Nakano, H., Ito, Y. and Kitamura, K. 1996. Oestradiol-induced relaxation of rabbit basilar artery by inhibition of voltage-dependent Ca channels through GTP-binding protein. Br. J. Pharmacol. 117, 351-359.   DOI
27 Sanders, K. M., Koh, S. D., Ro, S. and Ward, S. M. 2012. Regulation of gastrointestinal motility--insights from smooth muscle biology. Nat. Rev. Gastroenterol. Hepatol. 9, 633-645.   DOI
28 Sener, M. T., Sener, E., Tok, A., Polat, B., Cinar, I., Polat, H., Akcay, F. and Suleyman, H. 2012. Biochemical and histologic study of lethal cisplatin nephrotoxicity prevention by mirtazapine. Pharmacol. Rep. 64, 594-602.   DOI
29 Lee, H. T., Hennig, G. W., Park, K. J., Bayguinov, P. O., Ward, S. M., Sanders, K. M. and Smith, T. K. 2009. Heterogeneities in ICC Ca2+ activity within canine large intestine. Gastroenterology 136, 2226-2236.   DOI
30 Kim, B. J., So, I. and Kim, K. W. 2006. The relationship of TRP channels to the pacemaker activity of interstitial cells of Cajal in the gastrointestinal tract. J. Smooth Muscle Res. 42, 1-7.   DOI
31 Shuman, M., Chukwu, A., Veldhuizen, N. V. and Miller, S. A. 2019. Relationship between mirtazapine dose and incidence of adrenergic side effects: An exploratory analysis. Ment. Health Clin. 9, 41-47.   DOI
32 Camilleri, M. and Chang, L. 2008. Challenges to the therapeutic pipeline for irritable bowel syndrome: end points and regulatory hurdles. Gastroenterology 135, 1877-1891.   DOI
33 Choung, R. S., Cremonini, F., Thapa, P., Zinsmeister, A. R. and Talley, N. J. 2008. The effect of short-term, low-dose tricyclic and tetracyclic antidepressant treatment on satiation, postnutrient load gastrointestinal symptoms and gastric emptying: a double-blind, randomized, placebo-controlled trial. Neurogastroenterol. Motil. 20, 220-227.   DOI
34 de Boer, T. H., Nefkens, F., Van Helvoirt, A. and Van Delft, A. M. 1996. Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan. J. Pharmacol. Exp. Ther. 277, 852-860.
35 Demiryilmaz, I., Uzkeser, H., Cetin, N., Hacimuftuoglu, A., Bakan, E. and Altuner, D. 2013. Effect of mirtazapine on gastric oxidative stress and DNA injury created with methotrexate in rats. Asian J. Chem. 25, 2047.   DOI
36 Shahi, P. K., Choi, S., Zuo, D. C., Yeum, C. H., Yoon, P. J., Lee, J., Kim, Y. D., Park, C. G., Kim, M. Y., Shin, H. R., Oh, H. J. and Jun, J. Y. 2011. 5-hydroxytryptamine generates tonic inward currents on pacemaker activity of interstitial cells of cajal from mouse small intestine. Kor. J. Physiol. Pharmacol. 15, 129-135.   DOI
37 Tan, E., Smith, C. H. and Goldman, R. D. 2013. Antidepressants for functional gastrointestinal disorders in children. Can. Fam. Physician. 59, 263-264.
38 El-Tanbouly, D. M., Wadie, W. and Sayed, R. H. 2017. Modulation of TGF-β/Smad and ERK signaling pathways mediates the anti-fibrotic effect of mirtazapine in mice. Toxicol. Appl. Pharmacol. 329, 224-230.   DOI
39 Ford, A. C., Talley, N. J., Schoenfeld, P. S., Quigley, E. M. and Moayyedi, P. 2009. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 58, 367-378.   DOI
40 Grover, M., Farrugia, G., Lurken, M. S., Bernard, C. E., Faussone-Pellegrini, M. S., Smyrk, T. C. and NIDDK Gastroparesis Clinical Research Consortium. 2011. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology 140, 1575-1585.   DOI
41 Sperber, A. D., Bangdiwala, S. I., Drossman, D. A., Ghoshal, U. C., Simren, M., Tack, J., Whitehead, W. E., Dumitrascu, D. L., Fang, X., Fukudo, S., Kellow, J., Okeke, E., Quigley, E. M. M., Schmulson, M., Whorwell, P., Archampong, T., Adibi, P., Andresen, V., Benninga, M. A., Bonaz, B., Bor, S., Fernandez, L. B., Choi, S. C., Corazziari, E. S., Francisconi, C., Hani, A., Lazebnik, L., Lee, Y. Y., Mulak, A., Rahman, M. M., Santos, J., Setshedi, M., Syam, A. F., Vanner, S., Wong, R. K., Lopez-Colombo, A., Costa, V., Dickman, R., Kanazawa, M., Keshteli, A. H., Khatun, R., Maleki, I., Poitras, P., Pratap, N., Stefanyuk, O., Thomson, S., Zeevenhooven, J. and Palsson, O. S. 2021. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome foundation global study. Gastroenterology 160, 99-114.   DOI