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Prostanoid EP3 receptor agonist sulprostone enhances pacemaker activity of colonic interstitial cells of Cajal

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Abstract

EP receptor activation by PGE2 regulates gastrointestinal motility by modulating smooth muscle contractility. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate smooth muscle activity. We aimed to determine effects of the EP3 receptor agonist sulprostone on pacemaker potentials in colonic ICCs. We performed a whole cell patch clamp, RT-PCR, and Ca2+ imaging in cultured ICCs from mouse colon. Sulprostone depolarized the membrane and increased pacemaker frequency. EP3 receptor antagonist blocked these sulprostone-induced effects. EP3 receptors were expressed in ANO1-positive ICCs. Phospholipase C inhibitor or Ca2+-ATPase inhibitor from the endoplasmic reticulum blocked the sulprostone-induced effects and sulprostone increased intracellular Ca2+ ([Ca2+]i) oscillations. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers also suppressed the sulprostone-induced effects. Sulprostone enhanced pacemaker activity through EP3 receptors by activating HCN channels via the [Ca2+]i release pathway. Therefore, EP3 receptor activation in ICCs may modulate colonic motility and could be a therapeutic target for enhancing colonic GI motility.

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Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2015R1D1A1A01056819) and by the National Research Foundation of Korea grant (MRC, 2015-009070) funded by the Korea government (MSIP).

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  1. Man Woo Kim and Han Yi Jiao contributed equally to this work

Authors and Affiliations

  1. Department of Internal Medicine, College of Medicine, Chosun University, Gwangju, South Korea

    Man Woo Kim, Seok Won Kim & Chan Guk Park

  2. Department of Physiology, College of Medicine, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju, 501-375, South Korea

    Han Yi Jiao, Mei Jin Wu, Chansik Hong, Seok Choi & Jae Yeoul Jun

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  1. Man Woo Kim
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  2. Han Yi Jiao
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  8. Jae Yeoul Jun
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Correspondence to Jae Yeoul Jun.

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All animal handling and protocols in this study were performed in accordance with the guiding principles of the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by the ethics committee of Chosun University.

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The authors declare that they have no conflict of interest.

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Kim, M.W., Jiao, H.Y., Kim, S.W. et al. Prostanoid EP3 receptor agonist sulprostone enhances pacemaker activity of colonic interstitial cells of Cajal. Naunyn-Schmiedeberg's Arch Pharmacol 390, 961–969 (2017). https://doi.org/10.1007/s00210-017-1398-8

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  • DOI: https://doi.org/10.1007/s00210-017-1398-8

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