[논문]생쥐 소장 카할세포의 pacemaker potential에서 미르타자핀 효능에 관한 연구

김병주

doi:10.5352/jls.2021.31.7.662

[국내논문] 생쥐 소장 카할세포의 pacemaker potential에서 미르타자핀 효능에 관한 연구
Mirtazapine Regulates Pacemaker Potentials of Interstitial Cells of Cajal in Murine Small Intestine 원문보기

생명과학회지 = Journal of life science, v.31 no.7, 2021년, pp.662 - 670

초록
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카할세포는 위장관 근육의 pacemaker 세포이다. 이번 연구는 생쥐 소장에서 얻은 카할세포를 배양하여 노르아드레날린성 및 세로토닌성 항우울제인 미르타자핀의 효과를 조사했다. 전기생리학적인 방법을 이용하여 카할세포의 pacemaker potential의 변화를 측정하였다. 미르타자핀은 농도 의존적 방식으로 카할세포 탈분극을 일으켰다. Y25130 (5-HT3 수용체 길항제), RS39604 (5-HT4 수용체 길항제) 또는 SB269970 (5-HT7 수용체 길항제)은 미르타자핀에 의한 카할세포 탈분극에 영향을 미치지 않았다. 또한, 무스카린성 M2 수용체 길항제인 메톡 트라민은 미르타자핀에 의한 카할세포의 탈분극에 영향을 미치지 않은 반면, 무스카린성 M3 수용체 길항제인 4-DAMP는 카할세포의 탈분극을 억제하였다. GDP-β-S를 피펫을 통해 카할세포내로 넣었을 때, 미르타자핀에 카할세포 탈분극이 억제되었다. 외부에 칼슘이 없는 용액 또는 소포체의 Ca²⁺-ATPase 억제제인 thapsigargin이 있는 경우 미르타자핀에 의한 카할세포 탈분극이 나타났다. 또한, protein kinase C (PKC) 억제제인 칼포스틴 C 또는 chelerythrine은 미르타자핀에 의한 탈분극을 억제했습니다. 이러한 결과는 미르 타자핀이 카할세포에서 G 단백질 및 PKC 경로에 의한 무스카린성 M3 수용체 활성화를 통해 탈분극을 조절 함을 알 수 있다. 따라서 미르타자핀이 카할세포를 통해 위장관 운동성을 조절할 수 있음을 시사한다.

Abstract ▼ AI-Helper

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.

주제어

표/그림 (6)

그림 Fig. 1. Effects of mirtazapine on pacemaker potentials in cultured ICCs from the murine small intestine. (A-D) mirtazapine-induced pacemaker potential depolarization of ICCs (10-200 μM). (E) Summary of depolarization responses by mirtazapine. The values were expressed as the mean ± S.D. **p<0.01. CTRL, control.
그림 Fig. 2. Effects of 5-HT receptor subtype antagonists on mirtazapineinduced pacemaker potential depolarizations in cultured ICCs. (A) Pacemaker potential depolarization of ICCs exposed to mirtazapine in the presence of Y25130 5-HT₃ receptor antagonist (10 μM). (B) Pacemaker potential depolarization of ICCs exposed to mirtazapine in the presence of RS39604 5-HT₄ receptor antagonist (10 μM). (C) Pacemaker potential depolarization of ICCs exposed to mirtazapine in the presence of SB269970 5-HT₇ receptor antagonist (10 μM). (D) Summary of depolarization responses by mirtazapine in the presence of different 5-HT receptor antagonists. The values were expressed as the mean ± S.D. CTRL, control.
그림 Fig. 3. Effects of muscarinic receptor subtype antagonists on mirtazapineinduced pacemaker potential depolarizations in cultured ICCs. (A) Pacemaker potential depolarizations of ICCs exposed to mirtazapine in the presence of methoctramine muscarinic M₂ receptor antagonist (10 μM). (B) Pacemaker potentials of ICCs exposed to mirtazapine in the presence of 4DAMP muscarinic M₃ receptor antagonist (10 μM). Pacemaker potential depolarizations were inhibited. (C) Summary of depolarization responses by mirtazapine in the presence of different muscarinic receptor antagonists. The values were expressed as the mean ± S.D. **p<0.01. CTRL, control. Methoct, methoctramine. 4-DAMP, 4-diphenylacetoxy-N-methyl-piperidine methiodide.
그림 Fig. 4. Effects of GDP_βS on mirtazapineinduced pacemaker potential depolarizations in cultured ICCs. (A) Pacemaker potentials of ICCs exposed to mirtazapine in the presence of GDP_βS (1 mM) in the pipette. Under these conditions, mirtazapine-induced pacemaker potential depolarization was blocked. (B) Summary of depolarization responses by mirtazapine in the presence of GDP-β-S in the pipette. The values were expressed as the mean ± S.D. **p<0.01. CTRL, control. GDP-β-S, guanosine 5'-[β- thio] diphosphate.
그림 Fig. 5. Effects of external Ca²⁺ free solution or thapsigargin, a Ca²⁺-ATPase inhibitor of endoplasmic reticulum, on mirtazapineinduced pacemaker potential depolarizations in cultured ICCs. (A) External Ca²⁺ free solution eliminated the generation of pacemaker potentials. Under these conditions, mirtazapine depolarized pacemaker potentials. (B) Thapsigargin eliminated the generation of pacemaker potentials. In these conditions, mirtazapine depolarized pacemaker potentials. (C) Summary of depolarization responses by mirtazapine in the presence of external Ca²⁺ free solution or thapsigargin. The values were expressed as the mean ± S.D. **p<0.01. CTRL, control. Thapsi., Thapsigargin.
그림 Fig. 6. Effects of PKC inhibitors on mirtazapineinduced pacemaker potential depolarizations in cultured ICCs. (A) Calphostin C, a PKC inhibitor, blocked the mirtazapine-induced pacemaker potential depolarizations. (B) Chelerythrine, a PKC inhibitor, blocked the mirtazapine-induced pacemaker potential depolarizations. (C) Summary of depolarization responses by mirtazapine in the presence of PKC inhibitors. The values were expressed as the mean ± S.D. **p<0.01. CTRL, control.

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데이터처리

대조군과 실험군 사이의 통계학적 유의성 검정은 Student’s t-test를 사용하였으며 유의수준 p<0.05를 사용하였다
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참고문헌 (41)

Camilleri, M. and Chang, L. 2008. Challenges to the therapeutic pipeline for irritable bowel syndrome: end points and regulatory hurdles. Gastroenterology 135, 1877-1891.
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.
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.

상세보기
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.

상세보기
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.
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.

상세보기
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.
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.

상세보기
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.
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.
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.

상세보기
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.
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.

상세보기
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.

상세보기
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.

상세보기
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.
Inoue, R. and Chen, S. 1993. Physiology of muscarinic receptor-operated nonselective cation channels in guinea-pig ileal smooth muscle. EXS. 66, 261-268.

상세보기
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.
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.
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.
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.

상세보기
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.

상세보기
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.

상세보기
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.
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 Ca 2+ activity within canine large intestine. Gastroenterology 136, 2226-2236.
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.

상세보기
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.

상세보기
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.

상세보기
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.

상세보기
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.

상세보기
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.

상세보기
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.
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.

상세보기
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.
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.

상세보기
Tan, E., Smith, C. H. and Goldman, R. D. 2013. Antidepressants for functional gastrointestinal disorders in children. Can. Fam. Physician. 59, 263-264.
Thomas, S. G. 2000. Irritable bowel syndrome and mirtazapine. Am. J. Psychiatry 157, 1341-1342.
Timmer, C. J., Sitsen, J. M. and Delbressine, L. P. 2000. Clinical pharmacokinetics of mirtazapine. Clin. Pharmacokinet. 38, 461-474.

상세보기
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.
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.
Zhu, M. H., Kim, T. W., Ro, S., Yan, W., Ward, S. M., Koh, S. D. and Sanders, K. M. 2009. A Ca 2+ -activated Cl-conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. J. Physiol. 587, 4905-4918.

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